Drug Discovery: Alternative Approaches to

Lead Generation

S. J. Enna, Ph.D.

University of Perugia April 12th, 2016

Main Message

The Aim of a Drug Discovery Program is to …

Discover Drugs.

A word from the wise… “Reports that say that something hasn't happened are always interesting to me, because as we know, there are "known knowns"; there are things we know we know. We also know there are "known unknowns"; that is to say we know there are some things we do not know. But there are also "unknown unknowns" — the ones we don't know we don't know.“

Donald Rumsfeld

CNS Pharmacology Rankings in Comparison to Other

Subdisciplines

•  Known/Knowns: Low •  Known/Unknowns: High •  Unknown/Unknowns: Very High

Drug Discovery by Therapeutic Area+

Disease Area

Target-based Screening

Phenotypic Screening

Infectious diseases 3 7 Immune 1 0 Cancer 5 3 CNS 1 7 Metabolic 3 2 Cardiovascular 2 3 Gastrointestinal 1 1 Others 1 3 Rare diseases 0 2 Total 17 28

+ First-in-class small molecules approved by FDA 1999 - 2008* Adapted from Swinney, D.C. and Anthony, J., Nature Reviews-Drug Discovery, 10: 507-519, 2011

Organism Organ Cell Pathway Target Protein

Relationship between Assay Systems and Drug Discovery

- Ass

ay T

hrou

ghpu

t -

- Num

ber o

f Ass

umpt

ions

- - L

ead

Gen

erat

ion

Failu

re R

ate

- High

Low

- Assay System -

History of Drug Discovery

Paleo Era 199,840 years

Empirical Observation

Modern Era 160 years

Empirical Observation and Hypothesis Driven

Paleo Pharmaceuticals - Low Throughput -

•  Salicylates •  Opioids •  Cardiac Glycosides •  Gold Salts •  Hallucinogens •  Curare •  Ergot Alkaloids

Evolution of Research Strategies

Paleo Era Efficacy/Safety

Modern Era •  Physiology Period

Efficacy/Safety → Organ Systems Analysis

•  Biochemical Period Efficacy/Safety ↔ Cellular Analysis ↔ Organ System

•  Molecular Period Target Analysis → Cellular Analysis → Organ System → Efficacy/Safety

(Ligand Discovery)

targephilia \tär-gə-fil-yə\ n (2013) : Obsession with, and excessive focus on,

sites of drug action

Paleo Drug Discovery Flowchart

Consume

Live

Die

No Therapeutic Response

Therapeutic Response

Modern Drug Discovery Flowchart

Hopkins, A.L. et al., Nature 449:166-169, 2007

“Single Target Focus”

Some CNS Agents Launched with Unknown or Uncertain

Mechanism of Action •  Opioids •  General Anesthetics •  Barbiturates •  Benzodiazepines •  Phenothiazines •  Tricyclic Antidepressants •  Lithium •  Valproate •  Modafinil

Compound SAR

Known target / novel pharmacophore

Molecular Profile (e.g., Cerep screen)

Positive – Behavioral phenotype/ finger print

Acute pharmacometric screen (e.g., SmartCube™)

No activity

Leads

Additional in vivo profiling (behavior, electrophysiology.

microdialysis)

No further interest Chronic pharmacometric

screen (5-10 days bid)

Empirical Novel structures NCE Intermediates

Target specific NCEs (e.g., ACE inhibitor PPARγ inhibitor HDAC inhibitor)

Lead Optimization (efficacy, selectivity,

safety, DMPK, HERG, drugability)

No molecular profile* Lead

Candidates

IND

• No activity at molecular level

• “drug in search of a target”

“Patent Busting”

Known NCEs active at selected

target

Hits

Established / putative

drug target

Compound screening

Clin

ical

Dat

a Fe

edba

ck

Balanced Drug Discovery Flowchart

Drug Discovery Principles

•  An NCE is what it is, not what you want it to be

•  Knowledge of MOA is essential for optimizing a therapeutic class, but not for drug discovery

Back to the Future •  Increase emphasis on defining basic biology of

CNS function in intact animals

•  Increase emphasis on in vivo testing of NCEs from all therapeutic classes as possible CNS drug candidates – empirical observation

•  Identify sites of action of CNS drugs already known to be therapeutically useful

•  Increase training of scientists capable of executing and interpreting experiments in intact organisms

Adapted from Gary Larson