The Medicinal Chemist of Tomorrow

•4/28/2016

We will begin momentarily at 2pm ET

Slides available now! Recordings will be available to ACS members after one week.

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

1

Have Questions?

“Why am I muted?” Don’t worry. Everyone is muted except the presenter and host. Thank you and enjoy the show.

Type them into questions box! Contact ACS Webinars ® at [email protected]

2

•1

•4/28/2016

Have you discovered the missing element?

http://bit.ly/ACSjoin 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/ACSjoin

4

•2

•4/28/2016

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

facebook.com/acswebinars

@acswebinars

Search for “acswebinars” and connect!

5

How has ACS Webinars benefited you?

®

“Pharmacokinetic Considerations in Drug Design and Development was a very good webinar. It was clear, detailed and based in math which to me is what I need - credibility.” Quote in reference to: http://www.acs.org/content/acs/en/acswebinars/drug-discovery/pharmacokinetic.html

John Walls, Founder, Diversitec, LLC.

Be a featured fan on an upcoming webinar! Write to us @ [email protected]

6

•3

•4/28/2016

facebook.com/acswebinars

@acswebinars 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 one week after the Live broadcast date. 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

•4/28/2016

ChemIDP.org

Upcoming Events: • National Biotechnology Conference (NBC) – May 16th to 18th, Boston MA (http://www.aaps.org/nationalbiotech/)

www.aaps.org

10

•5

•4/28/2016

2016 Drug Design and Delivery Symposium

http://bit.ly/2016ddds

11

®

Upcoming ACS Webinars www.acs.org/acswebinars Thursday, May 5, 2016

Chemistry of Go: Solar Powered Flight Session 5 of the 2016 Material Science Series Claude Michel, Project Head for Solar Impulse, Solvay Mark Jones, Executive External Strategy and Communications Fellow, Dow Chemical

Thursday, May 12, 2016

Forensic Toxicology: Cracking the Case with Chemistry Jason Schaff, Forensic Chemist, United States Government Darren Griffin, Professor of Genetics, University of Kent, UK

Contact ACS Webinars ® at [email protected]

12

•6

•4/28/2016

2016 Drug Design and Delivery Symposium “The Medicinal Chemist of Tomorrow”

Molly Schmid

Joel Barrish

Ravi Nargund

Entrepreneur-in-Residence, Al Mann Institute Bioengineering, University of Southern California

Chief Scientific Officer, Achillion

Executive Director, Discovery Chemistry, Merck

Slides available now! Recordings will be available to ACS members after one week

www.acs.org/acswebinars The 2016 DDDS is co-produced with ACS Division of Medicinal Chemistry and the AAPS

13

The Medicinal Chemist of Tomorrow A Personal Perspective

Joel C. Barrish Ph.D. Executive Vice President & Chief Scientific Officer Achillion Pharmaceuticals

14

•7

•4/28/2016

Pharmaceutical Industry Challenges • • • • •

Regulatory Costs Cycle times Success rates Payers

Driving business/organizational Changes ……but also catalyzing a transformation in the science

– Budget, Accountability

15

Reasons to Believe • Drug therapies continue to be cost effective and will constitute a growing portion of global healthcare

• Chemistry plays a fundamental role • Success will depend on our ability to consistently innovate

16

•8

•4/28/2016

Audience Survey Question ANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENT

In 2015, how many small molecules (NMEs) and biologics (BLAs) were approved by the FDA?

•

15 NMEs and 6 BLAs

•

24 NMEs and 6 BLAs

•

33 NMEs and 12 BLAs

•

33 NMEs and 6 BLAs

17

Drug Discovery Innovation as a Function of Time Natural Products Isolation Plants

Microbes

(Semi) Synthesis Aspirin

Insects

Marine Life

Taxol Penicillins

“Un”natural Products “Rational” Design (Captopril) Structure-Based Design (Ritonavir-HIVPr; Apixiban-FXa)

“Inspired” Design (Dapagliflozin-SGLT2)

Biologics (Herceptin)

18

•9

•4/28/2016

Importance of Biological Target Selection Druggable Genome

Disease-modifying Genes Druggable Therapeutic Target Pool

New Chemical Approaches Better understanding of disease biology

Novel Biologics Platforms

Biologics 19

Targets Drive the Chemistry Strategy Deep Understanding of Biology

New Targets Classic approach, e.g. • Epigenetics • Regenerative Medicine • Immuno-oncology • RNA Modulation

Better understanding of Older Targets e.g. • GPCRs (Biased signaling) • Kinases (Covalent inhibitors) • Allosteric modulation

•

Ultimately, project success depends on the ability of the medicinal chemist to innovate

•

Our goal should be to have ‘Druggability’ disappear from our lexicon 20

•10

•4/28/2016

Targeting RNA ENCODE Modulating RNA Function: • microRNA/RNA complex • 5′/3′ UTRs • Pre-mRNA introns • lncRNAs/regulation of gene expression

ASOs

Small molecule approaches to targeting RNA motifs Nature Chemical Biology, 2014, 10, 291

Ribocil Nature, 2015, 526, 673

Demonstrating the potential • A bacterial riboswitch inhibitor

21

Targeting RNA: The Power of Small Molecules Gene

RNA (splice variant 1) – SMN1

RNA (splice variant 2) – SMN2

Proteinb

Proteina

Stable Protein

Science 345, 688 (2014)

Unstable Protein

22

•11

•4/28/2016

Alternative Binding Sites and Signaling Pathways GPCRs New structural information, along with improved tools in receptor pharmacology and mutagenesis, to drive understanding of: • agonism • allosteric modulation • dimerization • ligand-biased signaling Nature, 2011, 477, 549, 611

Protein Kinases Non-Active Site Inhibitors • Type III - e.g. PD MEK inhibitors, p38 (pyrazoloureas)

• Type IV/Regulatory Domains - e.g. Akt (PH), Bcr-Abl (myristoyl), CDK (cyclin), PLK (PDB) Future Med. Chem., 2011, 3, 29

Covalent/Irreversible Inhibitors

23

Targets Drive the Chemistry Strategy Deep Understanding of Biology

New Targets Classic approach, e.g. • Epigenetics • Regenerative Medicine • Immuno-oncology • RNA Modulation

Better understanding of Older Targets e.g. • GPCRs (Biased signaling) • Kinases (Covalent inhibitors) • Allosteric modulation

•

Ultimately, project success depends on the ability of the medicinal chemist to innovate

•

Our goal should be to have ‘Druggability’ disappear from our lexicon 24

•12

•4/28/2016

Not Just Small Heterocycles Anymore Target

Modality

RNA Function

Antisense Oligonucleotides

Tumor Antigens

Antibody Drug Conjugates (New linkers, conjugation methods; novel cytotoxics & affinity agents)

Protein-Protein Interactions

Peptides and derivatives Natural Products ‘Rule-Breakers ‘ (e.g. HCV NS5A) Daclatasvir MW = 738

DNA-encoded libraries, modified-peptides/proteins…. 25


How much time do you spend working on ‘non-traditional’ modalities (peptides, macrocycles, ASOs, ADCs, etc.)? •

Never

•

Rarely (less than 10 percent)

•

Often (greater than 25 percent)

•

It’s all I do

26

•13

•4/28/2016

Synthetic Chemistry Challenges

- Molecular Complexity and Portfolio Diversity • Increasing complexity of clinical candidates entering development – Driven by dependencies between biology, chemistry, and pharmaceutics • biology advances → increasingly sophisticated drug candidates • chemistry advances → accessibility/developability of complex structures • modern pharmaceutics → development of previously undevelopable assets

• Compound portfolios evolving to a mixture of modalities – e.g. small molecules, peptides, ADCs, oligos • All while focusing on ‘Speed to Patient’ – Accelerated chemistry optimization and scale-up • Discovery-Development transition is critical 27

Organizational Consequences • Organizations Can No Longer Do It All – Internal focus is a necessity

• Key Strategic Driver: Innovation through Alliances – A balanced approach to internal and external innovation • Academics, other companies, non-profits, government, CROs • Multiple models

• Matrix Teams, Both Internal and External, Increase in Importance – Balance between functional groups (Vertical) and program/portfolio teams (Horizontal) 28

•14

•4/28/2016

Medicinal Chemist of Tomorrow: Critical Competencies • Training – Medicinal vs. Organic Synthetic Chemistry – Focus on Synthesis & Physical Organic Chemistry (‘Must Have’), exposure to broad Biological Sciences (‘Nice to Have’) – Leadership

• ‘Problem Solvers’ vs. ‘Specialists’ – Continued focus on “traditional” small molecule training • strong background in general synthesis/methodology → fully adaptable to diverse structural modalities • subset of chemists with specialized training in new development modalities, e.g., peptide/proteins • demonstrated productivity, rapid problem solving → acceleration

• Non-Technical Keys to Success – Flexibility and adaptability – Ability to work in a matrix (internal and external) – Premium placed collaboration, cooperation, and communication, ability to influence • Integration, not isolation

– Crisp decision-making – ‘Fearlessness’

29

Additional References Recent FDA Approvals: Mullard, Nature Rev. Drug Disc., 2016, 15, 73 Why Drug Candidates Fail: Hay, Nature Biotech, 2014, 32, 40 “Druggable Genome”: Rask-Andersen, Nat. Rev. Drug Disc. 2011, 10, 579 RNA: Disney, Nature Chem. Biol., 2014, 10, 291; Roemer, Nature, 2015, 526, 673; Metzger, Peltz, Science 2014, 345, 688; Swalley, Sivasankaran, Nature Chem. Biol., 2015, 11, 511 Small Molecule Immuno-oncology: Hoos, Nature Rev. Drug Disc., 2015, 14, 603 Kinases: Ghosh, Curr. Pharm. Des., 2012, 18, 2936; Gray, Knapp, Nature Chem. Biol., 2015, 11, 818 GPCRs: Bouvier, Cell, 2012, 151, 14; Correll, McKittrick, J. Med. Chem., 2014, 57, 6887 “Middle Space”: Terrett, Med. Chem. Commun., 2013, 4, 474 Macrocyclic Peptides/Protein-Protein Interactions: Lokey, Nature Chem. Biol., 2011, 7, 810; Yin, Biopolymers Peptide Science, 2015, 104, 310 Molecular Complexity: Li, Eastgate, Org. Biomol. Chem., 2015, 13, 7164 30

•15

•4/28/2016

The Medicinal Chemist of Tomorrow…

Ravi P. Nargund, Ph.D. Executive Director, Discovery Chemistry Merck Research Laboratories, Kenilworth, NJ [email protected]

28th April 2016 31

32

The Discovery of New Medicines is Challenging! •

High quality, validated targets are rare

•

Discovering high quality candidates to develop is difficult

•

Development attrition is high

•

“It is harder to bring a new drug to market than to put a man on the moon”. Chris Hill, ACS Congress September 8th 2013, referring to the molecule that become the AIDS drug, Isentress.

•

“Putting a man on the moon is an engineering exercise. Isaac Newton knew the calculations. Whereas, if we’re discovering drugs, the problem is that we just don’t know enough. We really understand very little about human physiology. We don’t know how the machine works, so it’s not a surprise that when it’s broken, we don’t know how to fix it. The fact that we ever make a drug that gives favorable effects is a bloody miracle because it’s very difficult to understand what went wrong.” Roger Perlmutter, Forbes interview September 19th 2013.

32

•16

•4/28/2016


In which of the discovery & development phases 1 - 4, does medicinal chemistry have the potential for impact?

•

1 (Discovery)

•

1 - 2 (Discovery and Early Development)

•

1 - 3 (Discovery, Early Development, Late Development)

•

1 - 4 (Discovery, Early Development, Late Development, Lifecycle Management) 33

Drugs come as different Modalities

EDC 2015

34

•17

•4/28/2016

35

DRUG MODALITY: PROSPECTS Target space includes a broad scope of extracellular receptors and ion channels as well as an emerging vast number of intracellular protein-protein interactions, proteases, kinases, phosphatases, and other enzymes •Target Space Class

•“Undruggable” Intracellular

• (not comprehensive)

•• Cytokine Receptor •• Growth Factor Receptor •• T- and B-Cell Receptor •• Viral Fusion Receptor •• Ion Channel •• GPCR (class B) •• Transcription Factor •• Isomerase •• Polymerase •• Phosphatase •• Protease •• GPCR (class A) •• NHR •• Kinase

•Protein, •Monoclonal Antibody •mAb-drug Conjugate, •PEG-Peptide •Peptide, •Macrocycle, Proteomimetic

•Protein–Protein and Protein-DNA/RNA Interaction Targets

•Peptide, •Natural Product, •Small- •Peptidomimetic •molecule, Peptidomimetic

•500

•1000

•2000

•4000

•100,000

•MW

Modality Selection is a Strategy for Success •

36

Increasing share of non-small molecule modalities in the marketplace underscores their value as therapies

•

Diseases and targets can often be tackled with different modalities Understanding these modalities and selecting between them ensures we bring the best tool to the target Delivery technologies and earlier integration of medicinal chemistry with them is becoming increasingly important

•

•

•18

•4/28/2016

Medicinal Chemists are Entrepreneurial Drug Hunters: G Protein-Coupled Receptor Target Space

37

Known and orphan GPCRs relative to human genome mapping

•

•

A majority of known and orphan GPCRs are of the subfamily or class I category (“rhodopsin-like”) Existing GPCR-targeted drugs exemplify ~30% of the known GPCR superfamily

•

•

Also, they are predominantly of biogenic amine subtype of Class I

A potentially significant group is that represented by the peptide subtype of class I GPCRs.

Class III: known Class II: known Class III: orphans Class II: orphans Chalmers and Behan (2002) Nature Rev Drug Disc

Class I: known Class I: orphans

GHSR1a

SSTR2

(ghrelin)

Motlin

BRS3

MC4R

SSTR3

Other: known Other I: orphans

FFAR1

GLP1

GCGR

Reverse Pharmacology Approach in the discovery of MK-0677  Developed from enkephalin analogs.  Raised GH levels in animals and in man

NH N

H N

H2N O

O N H

HN

CH3 H N O

O N H

H N

O NH2

O

HN NH2 GHRP-6: His-D-Trp-Ala-Trp-D-Phe-Lys-NH2

H N

O

38

by injection.  Target and mechanism for GHRP-6 were unknown. Endogenous ligand was unknown. Bowers, C.Y.; et al. Endocrinol. 1980, 106, 663-667. Momany, F.A.; Bowers, C.Y. et al. Endocrinol. 1984, 114, 15311536.

NH2

OO N

MK-0677 (1995) N SO2CH3

Nargund, R. P.; et al. J. Med. Chem. 1998, 41, 3103. Patchett, A. A.; Nargund, R. P.; et al. PNAS 1995, 92, 7001.

• EC50 in rat pituitary cell assay MK-0677 = 1.3 nM; GHRP-6 = 10 nM • Pharmacokinetics in dogs F >60% ; t1/2 = 5 hr • Effective dosage to elevate GH in dogs: 25 mg/kg iv; 125 mg/kg po

•19

•4/28/2016

39

MK-0677 Multiple Doses 24 Hour GH Sampling: 72 Year Old Healthy Male 8 7

GH (mg/)

6

Pretreatment MK-0677 25 mg x 14 days

5

4 3 2 1 0

8 am 12 noon 4 pm

8 pm midnight 4 am Clock Time

8 am

In 1999 The Endogenous Ligand of the GH Secretagogue Receptor (GHS1a-R) Was Identified

40

Gly-Ser-OctSer-Phe-Leu-Ser-Pro-Glu-His-Gln-Arg-Val-Gln-Gln-Arg-Lys-Glu-Ser-LysLys-Pro-Pro-Pro-Ala-Lys-Leu-Gln-Pro-Arg Ghrelin

GHS1a IC50 = 0.25 + 0.07 nMa rat pit cell assay EC50 = 2.1 nM

    

(MK-0677 IC50 = 0.1 nM) (MK-0677 EC50 = 1.3 nM)

Ghrelin was isolated from stomach extracts GH elevation in rats @ 10 mg iv Octanoylation of Ser is essential for activity Present in human plasma @ 117.2 + 37.2 f mol ml-1 Food intake and weight gain are stimulated in rats and mice Cloning of receptor: Howard, A. D. et al., Science 1996, 273, 974 Natural ligand identification: Kojima, M. et al. Nature 1999, 402, 656-660. Inui, A. Nature Reviews/Neuroscience 2001, 2, 1-10

•20

•4/28/2016

41

Novel GLP1/Glucagon Receptor Co-Agonist Design • The GLP-1 and Glucagon Receptors are Family B GPCRs

•GCGR •GCG •GCGR

• GLP-1 and Glucagon Peptides Share ~45% Homology, with Similar Binding Modes

•N-terminus

•GCG

• Issues to be addressed by medicinal chemists: receptor balance, chemical/biophysical/metabolic stability and PK modulation GLP1

GCG

•Membrane

•C-terminus

•GCGR

•C-terminus

C III Interact with ECD

41

II

Alpha helix

I

Interact with 7TM

N

Lorenz, M. et al. Bioorg. Med. Chem. Lett. 2013, 23, 4011–4018


In terms of efficacy and financial impact, which of the above is the single most important diabetes drug class?

•

Tablets

•

GLP-1 class

•

Insulins

•

All of the above 42

•21

•4/28/2016

Insulin is the ultimate drug for treating diabetes and the single most important drug class

43

•Insulin release in normal and diabetic states

Zaykov, A. N. et al. Nature Reviews Drug Discovery 2016, advanced publication

44

Room for improvement of insulin therapy • Convenience (delivery) vs efficacy-safety (therapeutic index, TI) • Current insulin therapies are limited by its low intrinsic TI • As a result most patients are consistently undertreated – Failure to achieve treatment targets (HbA1c values) leads to high prevalence of atherosclerosis, retinopathy, neuropathy & nephropathy • A self-adjusting, “smart” insulin that (only) works at high ambient glucose concentrations has long been considered a “holy grail” of insulin therapy (Merck acquired SmartCells in 2010) 44

•22

•4/28/2016

Glucose-Responsive Insulin: Engineering Dual Affinity for Insulin and Lectin Receptors

45

•Insulin-Carbohydrate •Conjugate (ICC) •Insulin

•Lectin

•Receptor-Mediated •ICC Degradation


•Insulin Response •(glucose lowering)

•Insulin Receptor

45

•Lectin Receptor

46

Preferential Action on the Insulin Receptors at High Ambient Glucose Levels •Insulin-Carbohydrate Conjugate •Insulin

•Lectin



•Insulin Response •(glucose lowering)

•Glucose 46

•23

•4/28/2016

Collaboration Model Essential for Success Intellectual Property (Patent filings)

Protein Development & Engineering

Pharmacology

Process Chemistry

Biology & Chemical Biology Medicinal Chemistry

47

Separations

NEW MODALITY DEVELOPMENT

Catalysis & Biocatalysis

High throughput experimentation (HTE)

SM & Biologics Pharm. Sci.

Structural Chem. CROs and external resources

Analytical Chemistry

Academia & external collaborations

•Boutureira, O.; Bernardes, G. J. L. Chem. Rev. 2015, 115, 2174

48

The Tough Get Going! • Acknowledgments to “The Tough”: • All of the hundreds of scientists involved in our growth hormone secretagogue (Ghrelin-R agonist), GLP1/GCGR co-agonist and GRI programs • Particular thanks to the following for their input to this presentation: • Niels Kaarsholm • Tomi Sawyer • Robert Garbaccio 48

•24

•4/28/2016


Molly Schmid

Joel Barrish

Ravi Nargund






49

2016 Drug Design and Delivery Symposium

http://bit.ly/2016ddds

50

•25

•4/28/2016

®





51



Molly Schmid

Joel Barrish

Ravi Nargund






52

•26

•4/28/2016

Upcoming Events: • National Biotechnology Conference (NBC) – May 16th to 18th, Boston MA (http://www.aaps.org/nationalbiotech/)

www.aaps.org

53

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

54

•27

•4/28/2016

How has ACS Webinars benefited you?

®

“Pharmacokinetic Considerations in Drug Design and Development was a very good webinar. It was clear, detailed and based in math which to me is what I need - credibility.” Quote in reference to: http://www.acs.org/content/acs/en/acswebinars/drug-discovery/pharmacokinetic.html

John Walls, Founder, Diversitec, LLC.

Be a featured fan on an upcoming webinar! Write to us @ [email protected]

55

facebook.com/acswebinars @acswebinars youtube.com/acswebinars

Search for “acswebinars” and connect! 56

•28

•4/28/2016

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/ACSjoin

57

®

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.


58

•29

•4/28/2016

®






59

•30

The Medicinal Chemist of Tomorrow

Recommend Documents