Fighting Cancer: Targeting CNS Malignancy with Kinase

Gliadel and temozolomide (TMZ): Provide 1-2 month overall survival ... Part II: Steady state free drug concentration is the same on both sides of ...
46 downloads 7 Views 3MB Size
1/25/2017

We will begin momentarily at 2pm ET

Slides available now! Recordings available as an exclusive ACS member benefit.

www.acs.org/acswebinars Contact ACS Webinars ® at [email protected]

1

Have Questions?

Type them into questions box! “Why am I muted?” Don’t worry. Everyone is muted except the presenter and host. Thank you and enjoy the show. Contact ACS Webinars ® at [email protected]

2

1

1/25/2017

Have you discovered the missing element?

http://bit.ly/benefitsACS Find the many benefits of ACS membership! 3

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.

http://bit.ly/benefitsACS

4

2

1/25/2017

Let’s get Social…post, tweet, and link to ACS Webinars during today’s broadcast!

facebook.com/acswebinars

@acswebinars

Search for “acswebinars” and connect!

SBBD| Drew Medicinal Chemistry Course| 6.8.16

5

How has ACS Webinars ® benefited you?

“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.” http://bit.ly/TargetingRNA

Paul A. Craig, Professor and Head 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]

6

3

1/25/2017

youtube.com/acswebinars

Search for “acswebinars” and connect! 7

Learn from the best and brightest minds in chemistry! Hundreds of webinars presented by subject matter experts in the chemical enterprise. Recordings are available to current ACS members after the Live broadcast date via an invitation email. www.acs.org/acswebinars Broadcasts of ACS Webinars® continue to be available to the general public LIVE every Thursday at 2pm ET!

www.acs.org/acswebinars

8

4

1/25/2017

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

10

5

1/25/2017

Advances in the Pharmaceutical Sciences Series New and Upcoming Titles!

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

11

Catch up on Last Year’s Design and Delivery Symposium

http://bit.ly/2016ddds

12

6

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

13

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]

14

7

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

15

Fighting Cancer: Targeting CNS Malignancy with Kinase Inhibitors Timothy P. Heffron, Ph.D. January 26, 2017

8

1/25/2017

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

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

9

1/25/2017

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

20

10

1/25/2017

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)

21

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.

22

11

1/25/2017

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!

23

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.

24

12

1/25/2017

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.

25

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

13

1/25/2017

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.

28

14

1/25/2017

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?

29

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

7

AZD3759* achieves high free CNS penetration

*Specifically designed to achieve free brain penetration

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

30

15

1/25/2017

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

15

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.

31

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.

16

1/25/2017

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

33

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

17

1/25/2017

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.

36

18

1/25/2017

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 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.

38

19

1/25/2017

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.

39

PLK Inhibitor With Low Efflux Achieved Through Optimizing Physicochemical Properties

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

40

20

1/25/2017

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

42

21

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

44

22

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

24

1/25/2017

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

49

How has ACS Webinars ® benefited you?

“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.” bit.ly/TargetingRNA

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]

50

25

1/25/2017

youtube.com/acswebinars

Search for “acswebinars” and connect! 51

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.

http://bit.ly/benefitsACS

52

26

1/25/2017

®

ACS Webinars does not endorse any products or services. The views expressed in this presentation are those of the presenter and do not necessarily reflect the views or policies of the American Chemical Society.

Contact ACS Webinars ® at [email protected]

53

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]

54

27