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Thursday, May 12, 2016

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www.acs.org/acswebinars www.acs.org/acswebinars Slides available now! Recordings will be available to ACS members after one week

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

The 2016 DDDS is co-produced with ACS Division of Medicinal Chemistry and the AAPS

Joel Barrish Chief Scientific Officer,

Achillion

Molly Schmid Entrepreneur-in-Residence,

Al Mann Institute Bioengineering, University of Southern California

Ravi Nargund Executive Director,

Discovery Chemistry, Merck

The Medicinal Chemist of Tomorrow A Personal Perspective

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

Achillion Pharmaceuticals

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Pharmaceutical Industry Challenges

• Regulatory

• Costs

• Cycle times

• Success rates

• Payers

– Budget, Accountability

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

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

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

• 15 NMEs and 6 BLAs




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

Drug Discovery Innovation as a Function of Time

Natural Products

Isolation

Plants Microbes Insects Marine Life

(Semi) Synthesis

Aspirin Penicillins Taxol

“Un”natural Products

“Rational” Design (Captopril)

Structure-Based Design (Ritonavir-HIVPr; Apixiban-FXa)

Biologics (Herceptin)

“Inspired” Design (Dapagliflozin-SGLT2)

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Druggable Therapeutic Target Pool

Importance of Biological Target Selection

Novel Biologics Platforms

Biologics

New Chemical Approaches

Better understanding of disease biology

Druggable Genome

Disease-modifying Genes

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

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Targeting RNA

Nature Chemical Biology

Volume:

10,

Pages:

291–297

Year published:

(2014)

DOI:


Volume:

10,

Pages:

291–297

Year published:

(2014)

DOI:


Volume:

10,

Pages:

291–297

Year published:

(2014)

DOI:


Volume:

10,

Pages:

291–297

Year published:

(2014)

DOI:


Volume:

10,

Pages:

291–297

Year published:

(2014)

DOI:


Volume:

10,

Pages:

291–297

Year published:

(2014)

DOI:


Volume:

10,

Pages:

291–297

Year published:

(2014)

DOI:


Volume:

10,

Pages:

291–297

Year published:

(2014)

DOI:

ENCODE

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

Small molecule approaches to targeting RNA motifs

ASOs

Demonstrating the potential • A bacterial riboswitch inhibitor

Nature Chemical Biology, 2014, 10, 291

Ribocil Nature, 2015, 526, 673

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Targeting RNA: The Power of Small Molecules

Gene

RNA (splice variant 1) – SMN1 RNA (splice variant 2) – SMN2

Proteina Proteinb

Stable Protein Unstable Protein Science 345, 688 (2014) 22

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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

Future Med. Chem., 2011, 3, 29

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)

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

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Not Just Small Heterocycles Anymore

RNA Function Antisense Oligonucleotides

Tumor Antigens Antibody Drug Conjugates

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

Protein-Protein Peptides and derivatives

Interactions Natural Products

‘Rule-Breakers ‘ (e.g. HCV NS5A)

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

Target Modality

Daclatasvir MW = 738

25

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• Never

• Rarely (less than 10 percent)

• Often (greater than 25 percent)

• It’s all I do

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

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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)

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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

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Ravi P. Nargund, Ph.D.

Executive Director, Discovery Chemistry Merck Research Laboratories, Kenilworth, NJ

[email protected]

28th April 2016

The Medicinal Chemist of Tomorrow…

31

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

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• 1 (Discovery)

• 1 - 2 (Discovery and Early Development)

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

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

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

EDC 2015 34

Drugs come as different Modalities

http://www.sciencedirect.com/science/journal/01637258

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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

•MW

•Target Space Class • (not comprehensive)

•Peptide,

•Natural Product,

•Peptidomimetic •Small- •molecule,

Peptidomimetic

•500 •2000 •4000 •100,000

•Protein,

•Monoclonal Antibody

•mAb-drug Conjugate,

•PEG-Peptide

•“Undruggable”

Intracellular •Protein–Protein and

Protein-DNA/RNA

Interaction Targets

•1000

•Peptide,

•Macrocycle,

Proteomimetic

•• 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

DRUG MODALITY: PROSPECTS 35

Modality Selection is a Strategy for Success

• 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

36

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• 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 I: known

Class I: orphans

Class II: known

Class II: orphans

Class III: known

Class III: orphans

Other: known

Other I: orphans

Known and orphan GPCRs relative to human genome mapping

Motlin GCGR MC4R FFAR1 GLP1 SSTR3 BRS3 GHSR1a (ghrelin) SSTR2

Chalmers and Behan (2002) Nature Rev Drug Disc

Medicinal Chemists are Entrepreneurial

Drug Hunters: G Protein-Coupled

Receptor Target Space

37

Reverse Pharmacology Approach in the discovery of MK-0677

Developed from enkephalin analogs.

Raised GH levels in animals and in man

by injection.

Target and mechanism for GHRP-6

were unknown. Endogenous ligand was

unknown.

Nargund, R. P.; et al. J. Med. Chem. 1998, 41, 3103.

Patchett, A. A.; Nargund, R. P.; et al. PNAS 1995, 92, 7001.

H2NN

O

H

N

O

H

CH3

N

O

H

N

O

H

N

O

H

NH2

O

NH2

HNHN

NH

N

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

O

HN

O

NH2

N

O

N

SO2CH3

MK-0677

(1995)

• 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

Bowers, C.Y.; et al. Endocrinol. 1980, 106, 663-667.

Momany, F.A.; Bowers, C.Y. et al. Endocrinol. 1984, 114, 1531-

1536.

38

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

8 am 12 noon 4 pm 8 pm 4 am 8 am midnight

Clock Time

8

7

6

5

4

3

2

1

0

GH

(m

g/)

Pretreatment MK-0677 25 mg

x 14 days

39

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

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

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

Lys-Pro-Pro-Pro-Ala-Lys-Leu-Gln-Pro-Arg

Ghrelin

GHS1a IC50 = 0.25 + 0.07 nMa (MK-0677 IC50 = 0.1 nM)

rat pit cell assay EC50 = 2.1 nM (MK-0677 EC50 = 1.3 nM)

40

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Novel GLP1/Glucagon Receptor Co-Agonist Design

41

• The GLP-1 and Glucagon Receptors are Family

B GPCRs

• GLP-1 and Glucagon Peptides Share ~45%

Homology, with Similar Binding Modes

• Issues to be addressed by medicinal chemists:

receptor balance, chemical/biophysical/metabolic

stability and PK modulation

•GCGR •GCG

•GCGR •N-terminus

•GCGR •C-terminus

•Me

mb

rane

•GCG •C-terminus

Alpha helix

GLP1 GCG

C

III II I

N

Interact with 7TM

Interact with ECD

Lorenz, M. et al. Bioorg. Med. Chem. Lett.

2013, 23, 4011–4018

41

42


• Tablets

• GLP-1 class

• Insulins

• All of the above

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

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•Insulin release in normal and diabetic states

Insulin is the ultimate drug for treating diabetes and

the single most important drug class

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

43

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

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•Insulin

•Receptor-Mediated

•ICC Degradation

•Insulin Response

•(glucose lowering)

•Lectin


•ICC Degradation

•Insulin-Carbohydrate

•Conjugate (ICC)

•Insulin Receptor •Lectin Receptor

Glucose-Responsive Insulin: Engineering Dual

Affinity for Insulin and Lectin Receptors

45

Preferential Action on the Insulin Receptors at High Ambient Glucose Levels

46

•Insulin


•ICC Degradation

•Insulin Response

•(glucose lowering)

•Lectin


•ICC Degradation

•Insulin-Carbohydrate

Conjugate

•Glucose

46

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Collaboration Model Essential for Success

Intellectual Property (Patent filings)

Medicinal Chemistry

Process Chemistry

Biology &

Chemical Biology

Pharmacology

Separations

Catalysis &

Biocatalysis

Structural Chem.

Analytical Chemistry

SM & Biologics

Pharm. Sci.

CROs and

external resources

High throughput

experimentation (HTE)

Academia &

external collaborations

Protein Development

& Engineering

NEW MODALITY

DEVELOPMENT

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

47

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

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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

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

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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.”

John Walls,

Founder, Diversitec, LLC.

Quote in reference to: http://www.acs.org/content/acs/en/acs-

webinars/drug-discovery/pharmacokinetic.html

56


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Search for “acswebinars” and connect!

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

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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.

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the medicinal chemist of tomorrow - american chemical society · –balance between functional...

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