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2017 Drug Design and Delivery Symposium Save the Date for the next webinar!
“Fighting Cancer: Epigenetic Targets for Oncology” Stuart Conway, Professor of Organic Chemistry, University of Oxford
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Upcoming ACS Webinars www.acs.org/acswebinars Thursday, February 2, 2017
The Future of Flight: Advanced Renewable Jet Fuels Session 1 of the 2017 Industry Science Series Stanley Frey, R&D Fellow, Chemical Process Development, Honeywell Melody Bomgardner, Senior Business Editor, Chemical & Engineering News
Thursday, February 9, 2017
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2017 Drug Design and Delivery Symposium “Fighting Cancer: Targeting CNS Malignancy with Kinase Inhibitors”
Tim Heffron
Mark Wittman
Senior Scientist, Genentech
Senior Principal Scientist and Project Leader, Bristol-Myers Squibb
Slides available now! Recordings are an exclusive ACS member benefit.
www.acs.org/acswebinars The 2017 DDDS is co-produced with ACS Division of Medicinal Chemistry and the AAPS
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Fighting Cancer: Targeting CNS Malignancy with Kinase Inhibitors Timothy P. Heffron, Ph.D. January 26, 2017
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A Need for Improved Chemotherapeutics for Brain Cancer Brain Cancers
a) Primary brain tumors: >21,000 new brain cancer diagnoses/year (US)* Glioblastoma multiforme (GBM)**: •Most common, most aggressive primary CNS tumor in adults •Characterized by rapid growth and invasiveness •Median survival after diagnosis: ~14 months
*Ostrom, Q. T. et al. Neuro-Oncology 2013, 15 (Suppl. 2), 1-56. **Krex, D. et al. Brain 2007, 130, 2596-2606.
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A Need for Improved Chemotherapeutics for Brain Cancer Brain Cancers
a) Primary brain tumors: >21,000 new brain cancer diagnoses/year (US) Glioblastoma multiforme (GBM): •Most common, most aggressive primary CNS tumor in adults •Characterized by rapid growth and invasiveness •Median survival after diagnosis: ~14 months •Gliadel and temozolomide (TMZ): Provide 1-2 month overall survival benefit for patients with newly diagnosed GBM 18
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A Need for Improved Chemotherapeutics for Brain Cancer Brain Cancers
a) Primary brain tumors: >21,000 new brain cancer diagnoses/year (US)
b) Brain metastases: 20% - 40% of peripheral tumors develop brain metastases*
Glioblastoma multiforme (GBM): •Most common, most aggressive primary CNS tumor in adults
>150,000 new cases per year (US)*
•Characterized by rapid growth and invasiveness •Median survival after diagnosis: ~14 months •Gliadel and temozolomide (TMZ): Provide 1-2 month overall survival benefit for patients with newly diagnosed GBM
Brain Mets are a common resistance mechanism due to drug “sanctuary” in CNS 14% of patients with HER2+ Breast Cancer treated with pertuzumab progress due to brain mets**
*Patchell, R. A. Cancer Treat. Rev. 2003, 29, 533-540. **Swain, S. M. et al. Ann. Oncol. 2014, 25, 1116-1121.
How many small molecule kinase inhibitors were approved for cancer treatment through 2015? • Around 10 • Around 20
• Around 30 • Around 40 • Around 50
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Kinase Inhibitors Have Been Pursued for >30 Years
32 small molecule kinase inhibitors approved for cancer treatment (through 2015) None approved for treatment of primary CNS tumors. (alectinib has received accelerated approval to treat patients including those with brain metastases)
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Many Kinases Identified as Desirable Targets for Treating Brain Cancers Kinases for which biological rationale exists to target in brain cancer: VEGFR, PDGFR, EGFR, PI3K, mTOR, ALK, AKT, FGFR, IGF-1R, CDK4, CDK6, CDK1, CDK2, HER2, B-Raf, MEK, PLK1, Aurora, PKC, Abl, Src, Met, FAK, Pyk2, TGF-bR, PIM1, BTK, ATM, Axl, Mer Dozens of inhibitors of these kinases have been studied clinically in CNS cancers.
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Why Not More Success with Kinase Inhibitors in Treating CNS Cancers? • Need to freely penetrate Blood-Brain Barrier to reach tumors. • Until recently, there were no reports of kinase inhibitors designed specifically to address Brain Cancers. • Likely, in some cases free CNS penetration was purposely avoided. • Achieving free brain penetration with kinase inhibitors is challenging!
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Free Drug Hypothesis Part I: The free drug concentration at the site of action is the species that exerts pharmacological activity. Free drug concentration in the brain will drive efficacy
[Brain] or [Brain] / [Plasma] are less meaningful [Brain]u or [Brain]u / [Plasma]u should be used Requires measuring plasma protein and brain tissue binding as well as total concentrations.
Smith, D. A.; Di, L.; Kerns, E. H. Nat. Rev. Drug Disc. 2010, 9, 929.
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Free Drug Hypothesis Part II: Steady state free drug concentration is the same on both sides of any biomembrane. Key Exception: When efflux of drug occurs from the tissue of the therapeutic target (e.g. in the brain). Active transport (P-gp and Bcrp) is a primary limitation of CNS exposure for small molecule drugs.
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Smith, D. A.; Di, L.; Kerns, E. H. Nat. Rev. Drug Disc. 2010, 9, 929.
[Brain]/[Plasma] is Not Representative of Effective (free) Brain Penetration
Morphine-6glucuronide
Morphine
[Brain]/[Plasma] = 0.74 [Brain]/[Plasma] = 0.05 [Brain]u/[Plasma]u = 0.51 [Brain]u/[Plasma]u = 0.56 Molecules have comparable effects in vitro and in vivo. Rankovic, Z. J. Med. Chem. 2015, 58, 2584-2608.
Reported P-gp substrate:
Rat: [Brain]/[Plasma] = 1.3 [Brain]u/[Plasma]u = 0.1
Raub, T. et al. Drug Metab. Dispos. 2015, 43, 1360-1371.
Need 10x higher free plasma concentration to reach target free brain concentration
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Free Drug Considerations are Essential to Assess Merit of Drugs for Brain Cancer
Morphine-6glucuronide
Morphine
[Brain]/[Plasma] = 0.74 [Brain]/[Plasma] = 0.05 [Brain]u/[Plasma]u = 0.51 [Brain]u/[Plasma]u = 0.56 Molecules have comparable effects in vitro and in vivo. Rankovic, Z. J. Med. Chem. 2015, 58, 2584-2608.
Reported P-gp substrate:
Rat: [Brain]/[Plasma] = 1.3 [Brain]u/[Plasma]u = 0.1
This is a common scenario! 27
Raub, T. et al. Drug Metab. Dispos. 2015, 43, 1360-1371.
Excellent Perspectives on Considerations for CNS Drug Discovery: Rankovic, Z. J. Med. Chem. 2015, 58, 2584-2608. Di, L.; Rong, H.; Feng, B. J. Med. Chem. 2013, 56, 2-12.
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Many Kinases Identified as Desirable Targets for Treating Brain Cancers Kinases for which biological rationale exists to target for brain cancer:
VEGFR, PDGFR, EGFR, PI3K, mTOR, ALK, AKT, FGFR, IGF-1R, CDK4, CDK6, CDK1, CDK2, HER2, B-Raf, MEK, PLK1, Aurora, PKC, Abl, Src, Met, FAK, Pyk2, TGF-bR, PIM1, BTK, ATM, Axl, Mer Do clinical inhibitors of these targets evidently achieve free brain penetration?
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Several Kinase Targets Have Clinical-Stage Inhibitors with Potential for CNS Penetration Kinase Target
Clinical Inhibitors
Preclinical Free Brain Penetration
CDK4/6
3
Abemiciclib rat Kpuu, brain = 0.1
HER2
12
Tucatinib inhibits pHER2 in brain
MEK
15
Pimasertib, PD0325901 inhibit pERK in brain
ALK
9
PF06463922* acheives free brain penetration
PLK1
6
Abl/Src
7
TAK-960* not a P-gp substrate At least 3 achieve free brain penetration (brain PD, CSF-plasmau) Ibrutinib is not a P-gp substrate
BTK
multiple
PI3K
7 in CNS cancer trials
Buparlisib and GDC-0084* achieve free CNS penetration
mTOR
6 in CNS cancer trials
Palomid 529 not a P-gp substrate
EGFR
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AZD3759* achieves high free CNS penetration
*Specifically designed to achieve free brain penetration
Heffron, T. P. J. Med. Chem. 2016, 59, 10030-10066.
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Inadequate Free Brain Exposure of Clinical Kinase Inhibitors May Limit Efficacy in Brain Cancers Kinase Target
Clinical Inhibitors
VEGFR, PDGFR
15 in GBM trials
AKT FGFR IGF-1R CDK1/2 B-Raf
8 5 5 7 7
Aurora Kinases
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Preclinical Free Brain Penetration Cabozantinib and brivanib reportedly not P-gp substrates
None None None None None None
None PKC 4 None Met many None FAK/Pyk2 4 None TGFb-R 2 None PIM1 4 None ATM, Mer, Axl multiple Many kinase inhibitors have failed in brain cancer clinical trials— But untested clinical hypotheses remain due to lack of brain penetrant molecules. Heffron, T. P. J. Med. Chem. 2016, 59, 10030-10066.
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Challenges of Discovering Kinase Inhibitors for Brain Cancer 1. Need free brain penetration to engage target 2. Physical Properties of kinase inhibitors inconsistent with CNS drugs
However, physicochemical property optimization can lead to brain penetrant kinase inhibitors for brain cancer….. 32
*Wager et. al. ACS Chem. Neurosci. 2010, 1, 420-434.
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Approximately what percentage of Glioblastoma patients have been found to have pathway activation (PI3K, PTEN, EGFR)? • Around 50 Percent • Around 60 Percent • Around 70 Percent • Around 80 Percent • Around 90 Percent
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PI3K is a Compelling Target in a Key Pathway >80% of Glioblastoma patients have pathway activation (PI3K, PTEN, EGFR) • Pathway involvement associated with poor prognosis in lower grade gliomas
van der Heijden MS and Bernards R. Clin Cancer Res 2010; 16:3094-9.
• Brain metastases also driven by pathway activation
This pathway is central to numerous cancers via PTEN loss, PI3K mutations, Ras activation, RTK signaling,... 34
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Targeted Property Space for CNS Penetrating PI3K Inhibitors Identified minimum physicochemical property requirements for CNS penetration for a series of PI3K inhibitors (HBD ≤ 2, CNS MPO* ≥ 4.5, cLogP ≤ 1.5)
Genentech PI3K inhibitors targeting peripheral disease
cLogP
Molecules with desired properties for CNS penetration Molecules outside of desirable properties for CNS penetration
CNS MPO Score 35
Heffron, T. P.; et. al. J. Med. Chem. 2012, 55, 8007-8020. * Wager, T. et al. ACS Chem. Neurosci. 1, 2010, 420-434; 435-449.
GDC-0084 Achieves Desired Balance of Low Efflux, Potency, Metabolic Stability
GDC-0084 PI3K-a Ki
3 nM
2 nM
Cell prolif
PC3 = 0.33 uM
PC3 = 0.07 uM
MDR1 B-A/A-B
42
0.8
BCRP B-A/A-B
71
1.6
3 mL/min/kg
5 mL/min/kg
4
2
HLM Clhep HBD
Reducing HBD led to reduced efflux.
Heffron, T. P.; et. al. ACS Med. Chem. Lett. 2016, 7, 351-356.
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GDC-0084 Achieves Significant Free CNS Penetration, PD and Efficacy GDC-0084 GDC-0084
Values at 1 and 6h after 25 mg/kg po dose.
After 25 mg/kg po dose, GDC-0084 inhibits pAKT in normal brain tissue
GDC-0084 inhibits subcutaneous U87 tumor growth
Heffron, T. P.; et. al. ACS Med. Chem. Lett. 2016, 7, 351-356.
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Brain Penetrant EGFR Inhibitor Achieved Through Optimizing Physicochemical Properties Brain metastases emerge during EGFR inhibitor therapy. EGFR is a compelling target for glioblastoma treatment.
Zeng, Q.; et. al. J. Med. Chem. 2015, 58, 8200-8215.
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Brain Penetrant Macrocyclic ALK Inhibitor Identified Resistance to Crizotinib acquired through CNS metastases
Johnson, T. W.; et. al. J. Med. Chem. 2014, 57, 4720-4744.
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PLK Inhibitor With Low Efflux Achieved Through Optimizing Physicochemical Properties
Nie, Z.; et. al. Bioorg. Med. Chem. Lett. 2013, 23, 3662-3666.
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Kinase Inhibitors for Brain Cancer • Substantial unmet medical need (first and best in class opportunities) When kinase inhibitors are approved that lack CNS penetration, brain mets likely to emerge • Strong biological rationale Yet hypotheses have not been adequately tested with brain penetrant kinase inhibitors in the clinic • Previous failures of kinase inhibitors in brain cancer trials can be attributed to lack of CNS penetration • Better understanding now of CNS penetration requirements Brain penetrant kinase inhibitors are achievable through optimization of physicochemical properties Rankovic, Z. J. Med. Chem. 2015, 58, 2584-2608. Di, L.; Rong, H.; Feng, B. J. Med. Chem. 2013, 56, 2-12. 41
Acknowledgments GNE Discovery Chemistry
Argenta/Charles River Chemistry
GNE Translational Oncology
Alan Olivero Chudi Ndubaku Jennafer Dotson Sean Trapp Ignacio Aliagas Joy Drobnick Lan Wang Rich Goldsmith BinQing Wei
Robert Heald Steve Price Neville McLean Richard Bull Sussie Krintel
Heidi Philips Bruno Alicke Stephen Gould Joan Greve Dara Kallop Merry Nishimura
GNE DMPK Laurent Salphati Jodie Pang
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2017 Drug Design and Delivery Symposium “Fighting Cancer: Targeting CNS Malignancy with Kinase Inhibitors”
Tim Heffron
Mark Wittman
Senior Scientist, Genentech
Senior Principal Scientist and Project Leader, Bristol-Myers Squibb
Slides available now! Recordings are an exclusive ACS member benefit.
www.acs.org/acswebinars The 2017 DDDS is co-produced with ACS Division of Medicinal Chemistry and the AAPS
44
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1/25/2017
2017 Drug Design and Delivery Symposium Save the Date for the next webinar!
“Fighting Cancer: Epigenetic Targets for Oncology” Stuart Conway, Professor of Organic Chemistry, University of Oxford
45
Upcoming ACS Webinars www.acs.org/acswebinars Thursday, February 2, 2017
The Future of Flight: Advanced Renewable Jet Fuels Session 1 of the 2017 Industry Science Series Stanley Frey, R&D Fellow, Chemical Process Development, Honeywell Melody Bomgardner, Senior Business Editor, Chemical & Engineering News
Thursday, February 9, 2017
How to Make Chocolate for your Special Valentine: Flowers Bloom, Chocolate Shouldn't Rich Hartel, Professor of Food Engineering ,University of Wisconsin-Madison Bill Courtney, Culinary Chemist, Washington University School of Medicine
Contact ACS Webinars ® at
[email protected] 46
23
1/25/2017
2017 Drug Design and Delivery Symposium “Fighting Cancer: Targeting CNS Malignancy with Kinase Inhibitors”
Tim Heffron
Mark Wittman
Senior Scientist, Genentech
Senior Principal Scientist and Project Leader, Bristol-Myers Squibb
Slides available now! Recordings are an exclusive ACS member benefit.
www.acs.org/acswebinars The 2017 DDDS is co-produced with ACS Division of Medicinal Chemistry and the AAPS
47
Advances in the Pharmaceutical Sciences Series New and Upcoming Titles!
Find out more at: http://www.springer.com/series/8825?detailsPage=titles
48
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Join the ACS Division of Medicinal Chemistry Today!
For $25 ($10 for students), You Will Receive: • A free copy of our annual medicinal chemistry review volume (over 600 pages, $160 retail price) • Abstracts of MEDI programming at national meetings • Access to student travel grants and fellowships Find out more about the ACS MEDI Division! www.acsmedchem.org
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Paul A. Craig, Professor and Head of School of Chemistry & Materials Science, Rochester Institute of Technology ACS member for 33 years strong!
Be a featured fan on an upcoming webinar! Write to us @
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Benefits of ACS Membership Chemical & Engineering News (C&EN) The preeminent weekly news source.
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Upcoming ACS Webinars www.acs.org/acswebinars Thursday, February 2, 2017
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Thursday, February 9, 2017
How to Make Chocolate for your Special Valentine: Flowers Bloom, Chocolate Shouldn't Rich Hartel, Professor of Food Engineering ,University of Wisconsin-Madison Bill Courtney, Culinary Chemist, Washington University School of Medicine
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