Small molecule kinase inhibitors for the treatment of brain cancer

In addition to each of the factors that govern the identification of a successful oncology drug candidate, drug discovery aimed at treating neurological cancer must also consider the presence of the blood−brain barrier (BBB). The high level of expression of efflux transporters (e.g., Pglycoprotein (Pgp) and breast cancer resistance protein (Bcrp)) at the BBB limits many small molecules from freely reaching the brain, where neurooncologic malignancies reside. Furthermore, many of the targets identified for the potential treatment of central nervous system (CNS) malignancies suggest that kinase inhibitors, capable of penetrating the BBB to reach their target, would be desirable. This Perspective discusses the unmet need for neurooncology treatments, the appeal of kinase targets in this space, and a summary of what is known about free brain penetration of clinical inhibitors of kinases that are of interest for the treatment of brain cancer.

Perspective pubs.acs.org/jmc Small Molecule Kinase Inhibitors for the Treatment of Brain Cancer Timothy P Heffron* Genentech, Inc., DNA Way, South San Francisco, California 94080, United States S Supporting Information * ABSTRACT: In addition to each of the factors that govern the identification of a successful oncology drug candidate, drug discovery aimed at treating neurological cancer must also consider the presence of the blood−brain barrier (BBB) The high level of expression of efflux transporters (e.g., P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp)) at the BBB limits many small molecules from freely reaching the brain, where neurooncologic malignancies reside Furthermore, many of the targets identified for the potential treatment of central nervous system (CNS) malignancies suggest that kinase inhibitors, capable of penetrating the BBB to reach their target, would be desirable This Perspective discusses the unmet need for neurooncology treatments, the appeal of kinase targets in this space, and a summary of what is known about free brain penetration of clinical inhibitors of kinases that are of interest for the treatment of brain cancer ■ BACKGROUND Neurooncology encompasses the study of tumors that originate in the brain (e.g., glioblastoma multiforme (GBM)) as well as brain metastases In 2015, it was anticipated that more than 21 000 new cases of malignant brain and central nervous system (CNS) cancers would be diagnosed in the United States that year.1 Among malignant brain tumors, the most common is GBM which has an associated poor prognosis (3-year survival rate 3−5%).2 Despite the apparent unmet medical need, there has been little progress in developing new treatments for GBM Most evaluations of chemotherapeutics in GBM have failed Currently, the alkylating agents temozolomide (approved 2005) and the carmustine-based Gliadel wafer (approved 1996) are the only chemotherapeutics that are FDA approved for the treatment of newly diagnosed GBM Other neurological cancers have similarly limited drug treatment options In addition to the need for more treatment options for primary brain tumors, metastasis of tumors to the CNS occurs from as many as 40% of peripheral tumors, with well over 100 000 cases per year.3 When a kinase inhibitor is used for the treatment of peripheral disease, such CNS metastasis is a risk as a mechanism of emergent resistance if that inhibitor is not freely CNS penetrant In this scenario, treatment of a tumor with drug is effective until disease progression occurs in the CNS, where drug concentrations are limited As an example of the significance of the challenge presented by resistance due to CNS metastases, 14% of patients with HER2-positive breast cancer treated with pertuzumab had first evidence of disease progression due to CNS metastasis, evidently as a result of the inability of pertuzumab to cross the blood−brain barrier (BBB).4 Unfortunately, as discussed below, this scenario is not limited to HER2-positive disease treated with a therapeutic antibody but also happens with numerous FDA approved small molecule kinase inhibitors that not penetrate the CNS © 2016 American Chemical Society For CNS metastases, prognosis is generally poor and chemotherapy is useful only in limited settings,5 furthering the unmet need for new chemotherapeutics for malignancy in the CNS While primary brain tumors and brain metastases are distinct disease manifestations and may require targeting different drivers of disease, for the medicinal chemist, the approach to treating each of these indications requires the same considerations of the BBB, which typically limits small molecule penetration to the CNS where brain tumors reside Furthermore, for both primary and secondary brain tumors there is biological rationale to develop BBB penetrating kinase inhibitors While there have been 32 kinase inhibitors approved for the treatment of cancers that reside outside the CNS, no kinase inhibitor has been approved for the treatment of primary CNS tumors, while alectinib (61) has recently received accelerated approval to treat patients including those with brain metastases One reason for the lack of approved kinase inhibitors for treating brain tumors is that in order to effectively treat brain tumors, the kinase inhibitor must be capable of reaching its target Therefore, the kinase inhibitor must effectively cross the BBB As will be discussed below (and included as Supporting Information), the majority of approved kinase inhibitors and kinase inhibitors that have advanced to clinical study have no report of CNS penetration, reportedly limited CNS penetration, or CNS penetration that is expected to be limited due to the action of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) When considering potential therapeutics for the treatment of brain cancer, it is frequently asserted that because of disruption of the BBB by primary tumors or metastases in the brain, Received: April 21, 2016 Published: July 14, 2016 10030 DOI: 10.1021/acs.jmedchem.6b00618 J Med Chem 2016, 59, 10030−10066 Journal of Medicinal Chemistry Perspective molecules are not strong substrates of P-gp or Bcrp, efflux transporters highly expressed at the BBB.8,10 Small molecules that are significant substrates of P-gp are anticipated to have limited free CNS penetration, and in the discussion of clinical kinase inhibitors below, molecules that are reported to be P-gp substrates are suggested to likely have limited CNS penetration For medicinal chemists interested in kinase inhibitors to treat brain cancer, avoidance of P-gp transport must be a focus so as to maximize Kp,uu Considerations in the design of kinase inhibitors (or any small molecule) to limit transporter mediated efflux include a number of physicochemical properties that can be prospectively calculated Among the most critical properties to consider are the reported correlations between topological polar surface area (TPSA) and/or the number of hydrogen bond donors (HBD) and the likelihood of P-gp mediated efflux.8 ATP-competitive small molecule kinase inhibitors generally employ hydrogen bonding interactions with the hinge of the kinase, and oftentimes multiple hydrogen bond donors are utilized.11 As a result of the common use of frequent hydrogen bond donors within kinase inhibitors, overcoming the physicochemical property restraints that predict efflux while maintaining other desirable attributes of kinase inhibitors, including potency, is a challenge Indeed, a comparison of the median values of physicochemical properties of 119 CNS approved drugs12 with those for the 34 kinase inhibitors approved for clinical use (all indications) reveals significant disparities (Table 1) Whereas CNS drugs have a median value of HBD, consideration of the BBB is not relevant However, while it may be true that a tumor can disrupt the BBB, it generally does so just partially and significant literature reports indicate the importance of the BBB in limiting drug penetration to its intended target even when a tumor causes such partial disruption.6 Additionally, GBM in particular is noted to grow in a diffuse manner in which a significant portion of the tumor grows behind an intact BBB, and so without effective drugs that are capable of freely crossing that barrier the tumor progresses.7 That GBM grows in such a manner so as to remain behind an intact BBB punctuates the need for small molecules to be able to penetrate that barrier if they are to have potential to effectively treat that disease With an understanding of the importance of free BBB penetration for drugs targeting brain cancer, neurooncology medicinal chemistry programs have much in common with programs for other CNS diseases Fortunately, in recent years there has been a much improved appreciation for the requirement to achieve sufficient free drug concentration in the brain, if that is where the target resides A recent Perspective provides an excellent review of the concepts of free brain penetration that are essential to CNS and neurooncology programs alike and pertinent to the remainder of the discussion within.8 Succinctly, it is important to note that it is critical that kinase inhibitors that are intended to treat brain tumors achieve therapeutically beneficial f ree drug concentrations in the brain Indeed, a recent conference on CNS cancer drug discovery and development emphasized the need for neurooncology programs to focus on achieving free brain penetration.9 To assess in preclinical studies whether effective therapeutic concentrations of a molecule cross the BBB, and therefore whether it has a realistic chance of achieving efficacy by the intended mechanism, some assessment of free brain or, as a surrogate, cerebral spinal fluid (CSF) concentrations is needed.8 To assess the extent to which a small molecule freely penetrates the BBB (as opposed to just achieving a target free concentration in the brain), a comparison of free brain or CSF concentrations to free plasma concentrations is needed (Kp,uu) It is worth noting here that in the discussion of free brain penetration of clinical kinase inhibitors found below, the target therapeutic concentration is not often available, and so an assessment of free CNS penetration (Kp,uu or free brain-to-free plasma concentration ratios), where available, is utilized for an assessment Where such values were available, we considered values of 0.3 demonstrate a significant degree of free CNS penetration In principle, therapeutic free concentration of drug might be able to penetrate the BBB even with very low Kp,uu values In order for this to occur, however, there would need to be a corresponding increase in systemic exposure that might increase risk of unintended side effects To illustrate, a kinase inhibitor with a Kp,uu of 0.1 would require 10 times the sytemic exposure to achieve a therapeutic benefit in the brain compared to a kinase inhibitor equivalent in all aspects except for a Kp,uu of 1.0 When targeting CNS disease, then, the importance of maximizing Kp,uu is a significant consideration and likely to impact the safety/tolerability of a molecule at doses required to achieve therapeutically beneficial free concentrations in the CNS With an understanding of the importance of achieving free CNS penetration with molecules intended for the treatment of brain cancers, a paramount requirement for achieving significant free drug concentrations behind the BBB is that the small Table Comparison of Median Values of Physicochemical Properties for Kinase Inhibitors Approved for Clinical Use and 119 Drugs Approved for CNS Indications a b median property value approved kinase inhibitors (n = 34)a CNS drugs (n = 119)b cLogP cLogD7.4 TPSA (Å2) HBD MW pKa 4.2 3.6 91 483 7.0 2.8 1.7 45 305 8.4 Kinase inhibitors approved for any indication through 2015.13 Marketed CNS drugs Values obtained from ref 12 approved kinase inhibitors have Additionally, approved kinase inhibitors have a median TPSA value double that of approved CNS drugs Kinase inhibitors also tend to have significantly higher MW and lipophilicity than CNS drugs For more than 30 years, kinase inhibitors have been the focus of significant pharmaceutical pursuit and the appeal of kinase inhibitors as potential therapeutics extends to the treatment of brain tumors and metastases.14 While the nature of kinase inhibitors, particularly ATP competitive versions, may have some constraints on physical properties to achieve potency that are contrary to what is typical for CNS drugs, realizing potent kinase inhibitors that are capable of significant free brain penetration is possible However, free brain penetration has not been a design consideration for many kinase inhibitor programs and in some cases may have been intentionally avoided.15 Even when intentionally seeking potent and freely BBB penetrant kinase inhibitors, there are, of course, limitations to available in vivo brain cancer disease models in which such molecules can be studied and none “fully reflects human 10031 DOI: 10.1021/acs.jmedchem.6b00618 J Med Chem 2016, 59, 10030−10066 Journal of Medicinal Chemistry Perspective Table Structures and Key Properties for VEGFR and PDGFR Inhibitors Advanced to Clinical Study for Brain Cancera 10032 DOI: 10.1021/acs.jmedchem.6b00618 J Med Chem 2016, 59, 10030−10066 Journal of Medicinal Chemistry Perspective Table continued a Properties for 119 marketed CNS drugs are included for comparison *Median value of 119 marketed CNS drugs.12 gliomas.”16 As an example, the U87 model of glioblastoma is a frequently studied GBM model used in orthotopic mouse xenograft studies The use of the U87 model to assess whether or not a molecule has potential in the treatment of brain cancer is limited, however, as it is known to maintain a highly disrupted BBB, not relevant to clinical disease, and not to grow in the diffuse manner observed in human patients in which the tumor invades healthy brain with an intact BBB.17 For this reason, the U87 and potentially other models may overestimate the likelihood that an agent may provide therapeutic benefit in human GBM patients To understand whether the drug is capable of reaching its target in brain tissue, an evaluation of free brain-to-plasma ratios, free brain concentrations, change in brain concentration between wild-type mice and transporter knockout mice, or at least assessment of whether it is a substrate of P-gp or Bcrp is desirable The basis for the interest in kinase inhibitors to treat brain tumors begins with the underlying biology of CNS malignancy In the following sections, individual kinase targets with relevance in CNS malignancy are introduced In many cases kinase inhibitors have been studied in clinical trials of patients with brain tumors or metastases without success However, in many of those cases limited CNS penetration of the kinase inhibitor may have contributed to a lack of efficacy We identify clinical kinase inhibitors for the kinase targets, and within each section on a given kinase target, available data related to brain penetration of any clinical inhibitors of that target are summarized In the few cases where BBB penetrating inhibitors of a kinase target for brain cancer are reported, the medicinal chemistry efforts leading to this profile are discussed Ultimately, we summarize whether or not clinical brain penetrant inhibitors of kinase targets of interest for neurooncology are available Finally, a comparison of the physical properties of clinical CNS penetrant kinase inhibitors for brain cancer with those that have limited CNS penetration reveals remarkable similarity, and disparity from properties of CNS drugs its high expression in this context.20 Indeed, at least 14 inhibitors of VEGFR and/or PDGFR have been evaluated for their potential in the treatment of CNS tumors (Table 2), yet an unfortunate few would be expected to freely penetrate the BBB to reach such tumors Cediranib (1, Table 2)21 and pazopanib (2, Table 2)22 have been studied in phase II and phase III trials in GBM patients but did not show a survival benefit.23,24 The diffuse nature of GBM vasculature growth would require effective penetration of brain tissue by the inhibitors to maximize efficacy However, both cediranib and pazopanib have been reported to be substrates of both P-gp and Bcrp in vitro and these transporters were found to limit brain exposure in mice.25,26 Like cediranib and pazopanib, sunitinib (3),27 sorafenib (4),28 nintedanib (5),29 tivozanib (6),30 and dovitinib (7)31 were each ineffective in clinical GBM studies.32−36 Sunitinib, sorafenib, and nintedanib each are likely to have limited CNS penetration, as they are substrates of P-gp and/or Bcrp, whereas data are not available for tivozanib or dovitinib.37−39 Furthermore, for sorafenib, another study suggests that patients treated with renal cell carcinoma treated with sorafenib progress due to metastases only observed in the CNS, suggesting a sanctuary from drug due to lack of BBB penetration.40 Regorafenib (8, Table 2) demonstrated an effect in a rat model of glioblastoma41 and, accordingly, advanced to clinical studies for the treatment of GBM.42 While results are not available, efflux transport may limit free concentrations of regorafenib behind the BBB as the molecule is a substrate of P-gp and Bcrp and in P-gp/Bcrp knockout mice a 5.5-fold increase in brain concentration was achieved when compared to wild type mice at the same time point.43 The PDGFR-β, c-KIT, and Flt3 inhibitor tandutinib (9, Table 2) was found to be a substrate of both P-gp and Bcrp, which limits brain exposure in mice.44 Still, tandutinib was advanced to a phase I clinical trial in patients with GBM In that study, brain concentrations in patients were determined, and a mean brain-to-plasma ratio (total) in these patients was determined to be 0.33 However, no free brain-to-free plasma ratios or free brain concentration data from subsequent studies have been reported, and so no conclusion can be made about whether or not sufficient target engagment was achieved.45 After demonstrating in vivo efficacy in three different orthotopic GBM models in mice,46 axitinib (10, Table 2)47 encouragingly demonstrated activity in a phase II study of patients with GBM.48 However, it remains possible that the extent of benefit derived from axitinib treatment of GBM, where some tumor typically resides behind an intact BBB, may be limited due to the fact that axitinib is a significant substrate of P-gp and Bcrp This was demonstrated in mouse pharmacokinetic studies in which P-gp/Bcrp knockout mice had ■ VEGFR AND PDGFR Inhibition of angiogenesis has been established as a beneficial approach to treating cancer, and the potential of this approach to cancer treatment extends to cancers in the CNS.18 Targeting vascular endothelial growth factor receptors (VEGFRs) has been suggested to be of particular interest for the potential treatment of neurological tumors, as it is a known driver of angiogenesis in CNS tumors and found to be overexpressed in this setting, particularly the highly vascularized GBM.19 Additionally, platelet derived growth factor receptor (PDGFR), a kinase frequently inhibited by VEGFR inhibitors, has been identified as a potential target for the treatment of GBM due to 10033 DOI: 10.1021/acs.jmedchem.6b00618 J Med Chem 2016, 59, 10030−10066 Journal of Medicinal Chemistry Perspective of our knowledge, there are no reports of preclinical in vivo studies describing free brain exposure or clinical study results evaluating brivanib for the treatment of CNS tumors However, consistent with its lack of P-gp transport, cabozantinib has undergone a phase II study for the treatment of GBM and demonstrated some clinical and pharmacodynamic activity.62 Among the 15 VEGFR/PDGFR inhibitors discussed here and included in Table 2, just two have been reported to have minimal P-gp mediated efflux, of importance when targeting CNS malignancy That two, cabozantinib and brivanib, are able to minimize P-gp transport demonstrates that it is possible to achieve with still potent kinase inhibitors and enables assessment of the validity of the hypothesis that inhibiting their targets might be an effective treatment approach for GBM 14- and 21-fold increases in brain concentration at and h postdose when compared to wild type mice.49 Vandetanib (11, Table 2)50 and lenvatinib (12, Table 2)51 are additional VEGFR inhibitors that have advanced to clinical studies to treat GBM52,53 despite being reported substrates of P-gp.54,55 The ability to achieve efficacious free concentrations in the brain is a concern as P-gp efflux is anticipated to limit drug penetration to portions of tumor where the BBB remains intact Whether or not vatalanib (13, Table 2)56 is a substrate of P-gp or Bcrp in vitro has not been reported, and there are not reports of brain penetration of this molecule either preclinically or clinically Vatalanib was studied in phase I clinical trials in patients with glioma or GBM, but development of the molecule was halted prior to complete assessment in this patient population.57 Cabozantinib (14, Table 2)58 and brivanib (15, Table 2)59 stand out among the VEGFR inhibitors discussed here, as they are reported to not be substrates of P-gp transport, suggestive of their potential in the neurooncology setting.60,61 To the best ■ EGFR The initial success of the epidermal growth factor receptor (EGFR) inhibitors erlotinib (16, Table 3)63 and gefitinib (17, Table 3)64 in the treatment of EGFR mutant non-small-cell Table Structures and Key Properties for EGFR Inhibitors Advanced to Clinical Studya a Properties for 119 marketed CNS drugs are included for comparison *Median value of 119 marketed CNS drugs.12 10034 DOI: 10.1021/acs.jmedchem.6b00618 J Med Chem 2016, 59, 10030−10066 Journal of Medicinal Chemistry Perspective lung cancer (NSCLC) was followed by the approval of afatinib (18, Table 3)65 and more recently osimertinib (19, Table 3).66 In addition to their use in the treatment of NSCLC, erlotinib and gefitinib have been evaluated for the treatment of NSCLC brain metastases that harbor activating mutations of EGFR Despite some reported benefit of EGFR inhibitor treatment of EGFR mutant NSCLC brain metastases,67 it is also reported that such molecules are not as effective in the treatment of brain metastases as peripheral metastases, suggesting limited CNS penetration.68 In this scenario, the inhibitor may be able to effectively treat some, or a portion of, individual metastases where the BBB is compromised, yet lesions behind the BBB continue to grow Consistent with this theory, PET imaging of 11 C-erlotinib showed accumulation of drug in a brain metastasis but not in normal brain tissue These data suggest that where the BBB is intact, a “sanctuary” for tumor remains.69 That erlotinib was not capable of freely crossing the BBB was also established in a preclinical model of glioma.70 Gefitinib, afatinib, and osimertinib have each also been reported to be substrates of both P-gp and Bcrp, and so brain penetration of those EGFR inhibitors is expected to be limited.71−73 Nevertheless, what free concentration of afatinib that is capable of reaching CNS metastases in EGFR mutant-positive NSCLC has demonstrated benefit clinically.74 The interest in EGFR inhibitors for treating CNS cancer extends beyond brain metastases in NSCLC to GBM treatment In the most common and aggressive form of brain cancer, GBM, overexpression of EGFR is encountered in approximately 40% of patients and half of these have an associated extracellular mutation of EGFR (variant III).75 These factors suggest the potential utility of a brain penetrant EGFR inhibitor Several small molecule EGFR inhibitors, including gefitinib and erlotinib, have been approved for use in EGFR mutant NSCLC but, despite clinical study, have not resulted in approval for the treatment of gliomas.76 Investigation of brain penetrant inhibitors of EGFR would therefore be of interest For rociletinib (20, Table 3)77 no associated P-gp efflux or brain penetration data have been reported However, recently there have been two reports of EGFR inhibitors that, while maintaining the quinazoline core of earlier EGFR inhibitors, were reportedly designed to effectively penetrate the BBB to allow for effective treatment of CNS disease The first, NT113 (21, Table 3), a pan-ERBB inhibitor, demonstrated efficacy in intracranial GBM xeongrafts, including those with high EGFR vIII expression.78 A limitation in the characterization of 21 is that, while brain-to-plasma ratios are reported, no free brain concentrations or free brain-to-free plasma ratios are reported, limiting the interpretation of just how effectively this molecule penetrates the BBB Nevertheless, in intracranial GBM xenograft studies, 21 was more efficacious than either erlotinib or lapatinib, potentially indicating some improved degree of effective CNS penetration A second recently disclosed quinazoline-based clinical EGFR inhibitor intended to cross the BBB is AZD3759 (22, Table 3).79 The disclosure of 22 describes the directed effort toward specifically identifying a brain penetrating inhibitor of EGFR for the treatment of CNS tumors, particularly CNS metastases that arise in the course of treatment of EGFR mutant NSCLC In order to achieve the excellent brain penetration that 22 realizes compared to gefitinib (Figure 1), improving physical properties to reduce transporter mediated efflux was emphasized in the optimization effort In this case, the number of rotatable bonds had an apparent correlation with Figure Structural modifications upon gefitinib (17), focused on reducing rotatable bonds and effective hydrogen bond donors, led to the freely BBB penetrating inhibitor of EGFR, 22 efflux, and reduction of rotatable bonds, when compared to gefitinib, resulted in reduced transporter mediated efflux Furthermore, the fluorine atom of gefitinib was moved to be positioned next to the NH of the aniline in 22 (Figure 1) This positioning allows for intramolecular interaction of the F atom with the NH, thereby “masking” the HBD, commonly associated with increased transporter mediated efflux The structural modifications relative to gefitinib did not have an apparent detrimental impact on potency, as 22 and gefitinib are reported to have the same potency in a cellular assay employing an L858R EGFR mutant cell line, suggesting its potential in the treatment of NSCLC with EGFR mutant positive brain metastases The team at AstraZeneca demonstrated the effective penetration of 22 across the BBB in preclinical species by reporting both Kpuu,brain and Kpuu,CSF values that show that the molecule achieves equivalent free concentrations on each side of the barrier in rats The scientists at AstraZeneca went on to show extensive penetration of 22 into monkey brain in PET imaging studies 22 also demonstrated remarkable efficacy in an in vivo model of brain metastasis In this model, 22 clearly differentiates itself from erlotinib, which was not efficacious when administered at the same dose level as 22 While EGFR has been a long-standing target in GBM, previous molecules have not allowed for clinical conclusion on the validity of the target as transporter mediated efflux does not allow them to freely penetrate the BBB to where tumors reside The recent emergence of 21 and, particularly, 22 highlights an exciting opportunity to study inhibition of a known driver of a significant percentage of GBM cases and NSCLC brain metastases 21 and 22 are also part of a very limited set of kinase inhibitors reportedly specifically designed for the treatment of brain cancer ■ PI3K/AKT/mTOR In addition to targeting EGFR directly, another approach to treat GBM would be to target downstream kinases The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) kinases comprise one such pathway and are implicated in a significant percentage of GBM and neuroblastoma cases.80−83 Targeting the PI3K/AKT/mTOR pathway is also suggested as a mechanism to treat human epidermal growth factor receptor (HER2)-positive brain metastases.84 As a result of this biological implication and the pursuit of inhibitors of this pathway for other tumors, a number of agents have advanced to clinical trials in GBM patients.85 As the inhibitors of the PI3K/AKT/mTOR pathway have been reviewed in this context previously,85 we provide here a brief summary organized according to primary target of the inhibitor Of the many PI3K/mTOR inhibitors that have entered clinical study, GDC-0084 (25),86 buparlisib (26),87 PX-866 (28),88 10035 DOI: 10.1021/acs.jmedchem.6b00618 J Med Chem 2016, 59, 10030−10066 Journal of Medicinal Chemistry Perspective Table Structures and Key Properties for PI3K Inhibitors Advanced to Clinical Study for Brain Cancer or FDA Approveda a Properties for 119 marketed CNS drugs are included for comparison *Median value of 119 marketed CNS drugs.12 Figure Modifications of PI3K/mTOR inhibitors that resulted in the discovery of 25, a brain penetrating inhibitor with desirable metabolic stability pilaralisib (29),89 and XL765 (30)90 have been part of trials specifically for GBM (Table 4).83 Buparlisib has also advanced to clinical studies for the treatment of breast cancer patients with brain metastases.91 However, among these, only 25 was apparently designed to ensure significant free brain penetration In order to realize 25, a program was initiated to purposefully identify a PI3K/mTOR inhibitor capable of crossing the BBB so that it would be amenable to treating GBM These studies began with GNE-493 (23)92 as a starting point which was a potent inhibitor of PI3K and mTOR but was a substrate of P-gp and Bcrp (Figure 2).86 In order to realize brain penetrant analogs, the importance of reducing the number of hydrogen bond donors in 23 was identified as critical To further predict the likelihood of P-gp and Bcrp mediated efflux, as well as metabolic stability, in silico evaluations were used to prospectively evaluate designs From these efforts GNE-317 (24, Figure 2) was first identified which demonstrated that a brain penentrant PI3K inhibitor differentiated from a PI3K inhibitor that does not penetrate the BBB (2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno[3,2-d]pyrimidine (GDC-0941),93 not shown) in that it had a PD effect in normal brain tissue and had improved efficacy in in vivo brain tumor models.94 24 was found to have unacceptable projected human clearance and so was further optimized to 25 (Figure 2), a molecule 10036 DOI: 10.1021/acs.jmedchem.6b00618 J Med Chem 2016, 59, 10030−10066 Journal of Medicinal Chemistry Perspective The inhibitors 28, pilaralisib (29), and 30 have each progressed to clinical trials for the treatment of GBM, but there has not been a report of whether brain penetration was a design consideration or if these molecules penetrate the BBB The PI3K and PI3K/mTOR inhibitors discussed above inhibit each of the class I PI3K isoforms (α, β, δ, and γ) However, the only as yet approved PI3K inhibitor is idelalisib (31), a selective inhibitor of the δ isoform of PI3K.99 Idelalisib is approved for the treatment of chronic lymphocytic leukemia We were unable to identify any indications that CNS tumor progression is a mechanism of resistance to idelalisib This is a potential risk, as idelalisib is reported to not penetrate the BBB,100 consistent with the disclosure that it is a substrate of both P-gp and Bcrp.101 Among mTOR inhibitors, the mTORC1 inhibitors everolimus (32), temsirolimus (33), and sirolimus (34) are FDA approved agents (Table 5).102 Each of these molecules has been studied in patients with GBM but has not provided benefit.83 Perhaps insufficient brain penetration is a contributing factor to that is of comparable potency and has similar ability to cross the BBB to 24 but was projected to have more desirable human pharmacokinetic properties The ability of 25 to potently inhibit PI3K/mTOR signaling in the brain, along with its desirable projected human pharmacokinetic profile, led to its advancement to clinical trials for the treatment of GBM The report of the discovery of buparlisib (26) does not indicate that achieving brain penetration was a design consideration.87 However, in subsequent reports buparlisib has been reported to effectively cross the BBB and inhibit PI3K pathway signaling in preclinical95 and early clinical studies in patients with recurrent GBM.96 Unfortunately and despite inhibition of PI3K signaling in patient tumors, there was not substantial efficacy Additionally, buparlisib has been reported to cause mood changes, a side effect not observed with other PI3K inhibitors in the clinical setting.84 The structurally related dual PI3K/mTOR inhibitor PQR309 (27) is reported to not be a substrate of P-gp97 and achieves equivalent brain and plasma concentrations,98 although free concentrations were not reported Table Structures and Key Properties for mTOR Inhibitors Advanced to Clinical Study for Brain Cancera a Properties for 119 marketed CNS drugs are included for comparison *Median value of 119 marketed CNS drugs.12 10037 DOI: 10.1021/acs.jmedchem.6b00618 J Med Chem 2016, 59, 10030−10066 Journal of Medicinal Chemistry Perspective free brain concentrations, suggesting opportunity remains for AKT inhibitors that might be used to treat brain cancers the lack of efficacy, as everolimus and sirolimus are reported to be substrates of P-gp (and temsirolimus is a prodrug of sirolimus).103 AZD2014 (35)104 and CC-223 (36)105 are mTORC1/2 inhibitors that have advanced to GBM clinical trials.106,107 For 35, there is no indication of whether the molecule penetrates the BBB.108 In a clinical study of 36, GBM tumor-to-plasma ratios ranged from 16% to 77%.107 However, it is not possible to ascertain if sufficient concentrations to expect efficacy are achieved as free concentrations were not reported, including where the BBB is intact Most encouraging of the clinical mTOR inhibitors from the perspective of trying to treat brain cancer, palomid 529 (37) has been reported to effectively cross the BBB as brain concentrations were similar in pharmacokinetic experiments comparing wild type mice and P-gp knockout mice.109 This makes 37 one of a small set of clinical kinase inhibitors (the only apparent mTOR inhibitor) where limited brain penetration would not be a principal factor in limiting conclusion on the value of a target In addition to the inhibition of PI3K and mTOR, inhibition of AKT has received significant attention in this pathway.110 Among the clinical AKT inhibitors perifosine (38),111 8-(4-(1aminocyclobutyl)phenyl)-9-phenyl[1,2,4]triazolo[3,4-f ][1,6]naphthyridin-3(2H)-one (MK-2206, 125),112 PBI-05204 (39),113 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl3-butyn-2-ol (GSK690693),114 uprosertib,115 XL-418 (structure not disclosed), (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin1-yl)-3-(isopropylamino)propan-1-one (GDC-0068),116 and 3-(3-(4-(1-aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (ARQ-092),117 we were only able to identify some indication of the likelihood of brain penetration, or advancement to a clinical study for use in brain cancer, for perifosine and 39 (Table 6) Ultimately, the allosteric AKT inhibitor perifosine was part of a trial in GBM patients but did not demonstrate efficacy,83 consistent with limited (total) brain penetration preclinically.118 In a preclinical study of 39, significant total brain concentrations were achieved in rats but no assessment of free concentration was determined.119 Additionally, for 125, a trial of GBM patients was deemed not suitable due to “questions regarding the ability of the drug to pass through the blood−brain barrier”.83 Achieving brain penetration was not an apparent design consideration for any clinical AKT inhibitor, and no clinical AKT inhibitor is conclusively capable of achieving signficant ■ FGFR Fibroblast growth factor receptor (FGFR) kinase has been suggested as a potential target for the treatment of brain cancer,120,121 and numerous FGFR inhibitors have entered clinical development.122 As many of the FGFR inhibitors are nonselective, with many inhibiting VEGFR and PDGFR (discussed above), the focus of this section is limited to selective FGFR inhibitors that have entered clinical development (Table 7).123 Those inhibitors include AZD4547 (40),124 infigratinib (41),125 erdafitinib (42),126 CH5183284 (43),127 and ARQ 087 (structure not available) Of these, infigratinib has advanced to clinical studies in patients with GBM.128 However, we were unable to identify any data that suggest infigratinib is capable of penetrating the BBB Similarly, we were unable to identify data informing the potential of erdafitinib, 40, or 43 to freely cross the BBB On the other hand and of interest for its potential for the treatment of brain cancer, ARQ 087 was reported to achieve free brain-to-free plasma concentration ratios of about 0.1 in rats.129 ■ IGF-1R Type I insulin growth factor receptor (IGF-1R) has been identified as a potential target for the treatment of brain cancers,120,130 and numerous IGF-1R inhibitors have advanced to clinical trials.131 Among the clinical IGF-1R inhibitors (Table 8) linsitinib (44),132 BMS-754807 (45),133 BVP-51004 (46),134 XL-228 (47),135 and INSM-18 (48),136 there is no indication that achieving CNS penetration was a design consideration 45 was demonstrated to have limited total brain penetration in mouse studies,137 and 48 is believed to be a substrate of P-gp.138 We were unable to identify data related to efflux transport or brain penetration of the other IGF-1R inhibitors Unfortunately, the available data suggest that no clinical IGF-1R inhibitors are suitable to evaluate whether inhibition of this target would be beneficial for brain cancer treatment ■ CDKs In addition to aberrant EGFR and PI3K signaling pathways, activation of cyclin-dependent kinases (CDK) and is observed in a majority of GBM cases.82,139 Furthermore, CDK4/6 amplification is frequently observed in diffuse intrinsic pontine gliomas, a cancer of the brainstem.140 Among CDK4/6 inhibitors, Table Structures and Key Properties for Select AKT Inhibitors Advanced to Clinical Studya a Properties for 119 marketed CNS drugs are included for comparison *Median value of 119 marketed CNS drugs.12 10038 DOI: 10.1021/acs.jmedchem.6b00618 J Med Chem 2016, 59, 10030−10066 Journal of Medicinal Chemistry Perspective Table Structures and Key Properties for FGFR Inhibitors Advanced to Clinical Studya a compd primary kinase target HBD TPSA (A2) cLogP MW 40 41 42 43 CNS drugs* FGFR FGFR FGFR FGFR N/A 91 95 77 105 45 4.4 4.7 4.3 3.4 2.8 464 560 447 356 305 preclinical assessment of brain penetration no no no no data data data data reported reported reported reported Properties for 119 marketed CNS drugs are included for comparison *Median value of 119 marketed CNS drugs.12 Table Structures and Key Properties for IGF-1R Inhibitors Advanced to Clinical Studya a Properties for 119 marketed CNS drugs are included for comparison *Median value of 119 marketed CNS drugs.12 palbociclib (49, Table 9)141 is approved for the treatment of hormone-receptor positive breast cancer Regarding its potential for the treatment of brain cancer, palbociclib was demonstrated to provide a survival benefit in a genetic mouse model of brainstem glioma.142 Preclinical studies in three intracranial mouse models of GBM showed that palbociclib was efficacious either as a single agent or in combination with radiation.143 However, palbociclib was found at 25-fold higher concentration in tumor than in normal brain tissue, suggesting that the molecule has limited penetration into the brain and the BBB is compromised at the core of the tumor but not in normal brain tissue Therefore, despite the reports of efficacy in brain cancer models, palbociclib may have free brain concentrations below what is needed for efficacy in tumors where the BBB is intact This would be consistent with being a substrate of P-gp,144 and ultimately an assessment of free brain concentrations or Kpuu,brain is necessary to draw a conclusion about the merits of palbociclib for use in brain cancer Like palbociclib, abemaciclib (50)145 is reported to be a substrate of both P-gp and Bcrp.146 However, in mice and rats, Kpuu,brain is measurable at at least 0.2 and, while perhaps a model of modest utility, abemaciclib demonstrated efficacy in an orthotopic U87 GBM model in rats.146,147 While there is potential to further increase free brain penetration, given that some free brain exposure is attained with abemaciclib, it is encouraging that a trial studying abemaciciblib in breast cancer, 10039 DOI: 10.1021/acs.jmedchem.6b00618 J Med Chem 2016, 59, 10030−10066 Journal of Medicinal Chemistry Perspective protein kinase B; mTOR, mammalian target of rapamycin; HER2, human epidermal growth factor receptor 2; FGFR, fibroblast growth factor receptor; IGF-1R, type I insulin growth factor receptor; CDK, cyclin-dependent kinase; ALK, anaplastic lymphoma kinase; MEK, mitogen activated protein kinase; PLK, Polo-like kinase; PKC, protein kinase C; Ph+, Philadelphia chromosome positive; CML, chronic myeloid leukemia; ALL, acute lymphoblastic leukemia; FAK, focaladhesion kinase; Pyk2, proline rich tyrosine kinase 2; TGFβ-R, transforming growth factor receptor β; BTK, Bruton’s tyrosine kinase; MCL, mantle cell lymphoma; ATM, ataxia telangiectasia mutated of brain metastases is expected when the treatments are not BBB penetrant (e.g., ALK, HER2, EGFR, etc.) Whereas in discovery programs brain penetration might be considered a liability for potential CNS safety reasons, limiting brain penetration might ultimately result in a resistance mechanism clinically via brain metastasis In this scenario, best-in-class opportunities may emerge where brain penetrating kinase inhibitors can be realized Whether for primary brain cancers or brain metastases, that so few kinase inhibitors have been reportedly designed to achieve CNS penetration suggests that the lack of advancement in the treatment of brain cancers has been at least in part due to lack of directed effort with an appreciation of free drug principles At the same time, that CNS penetrant inhibitors of various kinases have been identified, and specifically designed and realized, demonstrates that success in this area can be achieved, even if the physicochemical properties of kinase inhibitors and those of CNS drugs at first appear at odds The clear medical need, biological rationale, and improved appreciation for free drug principles provide an impetus and framework to properly approach the challenge of discovering and developing kinase inhibitors for brain cancer ■ ■ ASSOCIATED CONTENT S Supporting Information * The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.6b00618 Calculated physicochemical properties of FDA approved kinase inhibitors and of discussed inhibitors that are capable of penetrating the BBB or have limited CNS penetration (PDF) ■ REFERENCES (1) Ostrom, Q T.; Gittleman, H.; Farah, P.; Ondracek, A.; Chen, Y.; Wolinsky, Y.; Stroup, N E.; Kruchko, C.; Barnholtz-Sloan, J S CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2006−2010 Neuro-Oncology 2013, 15 (Suppl 2), 1−56 (2) Krex, D.; Klink, B.; Hartmann, C.; von Deimling, A.; Pietsch, T.; Simon, M.; Sabel, M.; Steinbach, J P.; Heese, O.; 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no competing financial interest Biography Timothy P Heffron is a Senior Scientist at Genentech As a medicinal chemist and chemistry and research team leader, Timothy has contributed to the advancement of programs directed toward treatments for neurooncology, oncology (including cancer immunotherapy), neurology, and ophthalmology indications Timothy has contributed to seven molecules that have advanced to clinical development, four of which came under his leadership as a chemistry team leader, including taselisib (phase III) Timothy completed his undergraduate studies in chemistry at Yale University and his doctoral studies at The Massachusetts Institute of Technology ■ ACKNOWLEDGMENTS Cyrus Khojasteh, Xingrong Liu, and Alan Olivero are acknowledged for their helpful comments in the preparation of this Perspective ■ ABBREVIATIONS USED GBM, glioblastoma multiforme; CNS, central nervous system; BBB, blood−brain barrier; CSF, cerebral spinal fluid; P-gp, P-glycoprotein; Bcrp, breast cancer 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