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www.acs.org/acswebinars Slides available now! Recordings are an exclusive ACS member benefit.

2017 Drug Design and Delivery Symposium

“Fighting Cancer: Targeting CNS Malignancy with Kinase Inhibitors”

The 2017 DDDS is co-produced with ACS Division of Medicinal Chemistry and the AAPS

Tim Heffron Senior Scientist,

Genentech

Mark Wittman Senior Principal Scientist and Project

Leader, Bristol-Myers Squibb

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. 17


Brain Cancers


>21,000 new brain cancer diagnoses/year (US)

Glioblastoma multiforme (GBM):


tumor in adults



•Gliadel and temozolomide (TMZ):

Provide 1-2 month overall survival benefit for

patients with newly diagnosed GBM

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Brain Cancers


>21,000 new brain cancer diagnoses/year (US)

Glioblastoma multiforme (GBM):


tumor in adults



•Gliadel and temozolomide (TMZ):

Provide 1-2 month overall survival benefit for

patients with newly diagnosed GBM

b) Brain metastases: 20% - 40% of peripheral tumors develop brain metastases* >150,000 new cases per year (US)* 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

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

Kinases for which biological

rationale exists to target in

brain cancer:

Dozens of inhibitors of these kinases have been studied

clinically in CNS cancers.

22

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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

Smith, D. A.; Di, L.; Kerns, E. H. Nat. Rev. Drug Disc. 2010, 9, 929.

[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.

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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.

Smith, D. A.; Di, L.; Kerns, E. H. Nat. Rev. Drug Disc. 2010, 9, 929. 25

[Brain]/[Plasma] is Not Representative of Effective (free) Brain Penetration

Molecules have comparable effects in vitro and in vivo. Rankovic, Z. J. Med. Chem. 2015, 58, 2584-2608.

[Brain]/[Plasma] = 0.74

[Brain]u/[Plasma]u = 0.51



Morphine

Morphine-6-

glucuronide

Rat:



Raub, T. et al. Drug Metab. Dispos. 2015, 43, 1360-1371.

Reported P-gp

substrate:

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

Molecules have comparable effects in vitro and in vivo.





Rat:



Raub, T. et al. Drug Metab. Dispos. 2015, 43, 1360-1371.

Reported P-gp

substrate:

This is a common scenario!

Rankovic, Z. J. Med. Chem. 2015, 58, 2584-2608.

Morphine

Morphine-6-

glucuronide

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Excellent Perspectives on Considerations for

CNS Drug Discovery:


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

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

Kinases for which biological rationale exists

to target for brain cancer:

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

EGFR 7 AZD3759* achieves high free CNS

penetration

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

CDK4/6 3 Abemiciclib rat Kpuu, brain = 0.1

HER2 12 Tucatinib inhibits pHER2 in brain

MEK 15 Pimasertib, PD0325901 inhibit pERK in

brain

PLK1 6 TAK-960* not a P-gp substrate

Abl/Src 7 At least 3 achieve free brain penetration

(brain PD, CSF-plasmau)

BTK multiple Ibrutinib is not a P-gp substrate

ALK 9 PF06463922* acheives free brain

penetration

*Specifically designed to achieve free brain penetration

Heffron, T. P. J. Med. Chem. 2016, 59, 10030-10066.

Kinase Target Clinical Inhibitors Preclinical Free Brain Penetration

30

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Inadequate Free Brain Exposure of Clinical Kinase Inhibitors May Limit Efficacy in Brain Cancers

Kinase Target Clinical Inhibitors Preclinical Free Brain Penetration

AKT 8 None

FGFR 5 None

IGF-1R 5 None

CDK1/2 7 None

B-Raf 7 None

Aurora Kinases 15 None

PKC 4 None

Met many None

FAK/Pyk2 4 None

TGFb-R 2 None

PIM1 4 None

ATM, Mer, Axl multiple None

Many kinase inhibitors have failed in brain cancer clinical trials—

But untested clinical hypotheses remain due to

lack of brain penetrant molecules.

VEGFR, PDGFR 15 in GBM trials Cabozantinib and brivanib reportedly not

P-gp substrates

Heffron, T. P. J. Med. Chem. 2016, 59, 10030-10066. 31

1. Need free brain penetration to engage target

2. Physical Properties of kinase inhibitors inconsistent with CNS drugs

Challenges of Discovering Kinase Inhibitors for Brain Cancer

*Wager et. al. ACS Chem. Neurosci. 2010, 1, 420-434.

However, physicochemical property optimization can lead to brain penetrant

kinase inhibitors for brain cancer…..

32

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Approximately what percentage of Glioblastoma patients have been found to have pathway activation (PI3K, PTEN, EGFR)?

• Around 50 Percent





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PI3K is a Compelling Target in a Key Pathway

This pathway is central to numerous cancers via PTEN

loss, PI3K mutations, Ras activation, RTK signaling,...

This pathway is central to numerous cancers via PTEN

loss, PI3K mutations, Ras activation, RTK signaling,...

van der Heijden MS and Bernards R. Clin Cancer Res 2010; 16:3094-9.

>80% of

Glioblastoma

patients have

pathway activation

(PI3K, PTEN, EGFR)

• Pathway

involvement

associated with poor

prognosis in lower

grade gliomas

• Brain metastases

also driven by

pathway activation

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)

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.

Molecules with

desired properties

for CNS

penetration

Molecules outside

of desirable

properties for CNS

penetration

Genentech PI3K inhibitors targeting peripheral disease cLogP

CNS MPO Score

35

GDC-0084 Achieves Desired Balance of Low Efflux, Potency, Metabolic Stability

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

HLM Clhep 3 mL/min/kg 5 mL/min/kg

HBD 4 2

GDC-0084

Reducing HBD led to reduced efflux.

Heffron, T. P.; et. al. ACS Med. Chem. Lett. 2016, 7, 351-356. 36

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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. 37

Brain Penetrant EGFR Inhibitor Achieved Through Optimizing Physicochemical Properties

Zeng, Q.; et. al. J. Med. Chem. 2015, 58, 8200-8215.

Brain metastases emerge during EGFR inhibitor therapy.

EGFR is a compelling target for glioblastoma treatment.

38

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Brain Penetrant Macrocyclic ALK Inhibitor Identified

Johnson, T. W.; et. al. J. Med. Chem. 2014, 57, 4720-4744.

Resistance to Crizotinib acquired

through CNS metastases

39

PLK Inhibitor With Low Efflux Achieved Through Optimizing Physicochemical Properties

Nie, Z.; et. al. Bioorg. Med. Chem. Lett. 2013, 23, 3662-3666. 40

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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


Di, L.; Rong, H.; Feng, B. J. Med. Chem. 2013, 56, 2-12.

41

Acknowledgments

GNE Discovery

Chemistry

Alan Olivero

Chudi Ndubaku

Jennafer Dotson

Sean Trapp

Ignacio Aliagas

Joy Drobnick

Lan Wang

Rich Goldsmith

BinQing Wei

GNE DMPK

Laurent Salphati

Jodie Pang

GNE Translational

Oncology

Heidi Philips

Bruno Alicke

Stephen Gould

Joan Greve

Dara Kallop

Merry Nishimura

Argenta/Charles

River Chemistry

42

Robert Heald

Steve Price

Neville McLean

Richard Bull

Sussie Krintel

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Genentech



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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


46








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Genentech



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Find out more at: http://www.springer.com/series/8825?detailsPage=titles

Advances in the Pharmaceutical Sciences Series New and Upcoming Titles!

http://www.springer.com/series/8825?detailsPage=titles

1/25/2017

25

49 Find out more about the ACS MEDI Division! www.acsmedchem.org

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

50

“I am interested in creating academic programs in rational drug design. This webinar was great and I will definitely be watching the other videos in the series.” 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 @ [email protected]

How has ACS Webinars benefited you?

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youtube.com/acswebinars


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Benefits of ACS Membership


Chemical & Engineering News (C&EN) The preeminent weekly news source.

NEW! Free Access to ACS Presentations on Demand® ACS Member only access to over 1,000 presentation recordings from recent ACS meetings and select events.

NEW! ACS Career Navigator Your source for leadership development, professional education, career services, and much more.

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