Prof

. Jos

hua

Kritz

er, T

ufts

Uni

vers

ity

Pete

Tur

ner

The Quest for a Cure: Introduction toDrug Discovery

Prof. Joshua KritzerApril 13, 2020

joshua.kritzer@tufts.edu@ChemKritzer

https://ase.tufts.edu/chemistry/kritzer/kritzerlab1.html

Prof

. Jos

hua

Kritz

er, T

ufts

Uni

vers

ity

My journey

BE Chemical Engineering The Cooper Union

PhD Biophysical ChemistryYale University

Postdoc in Genetics and Cell BiologyWhitehead Institute

Prof

. Jos

hua

Kritz

er, T

ufts

Uni

vers

ity

Introduction to Drug Discovery

Part 1 What are drugs?How drugs work History of drug discovery

Part 2 Methods of drug discoveryNatural productsHigh-throughput screening Structure-based designBiopharmaceuticalsGenetic therapies

Part 3 Current challenges in drug discovery

Prof

. Jos

hua

Kritz

er, T

ufts

Uni

vers

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What are drugs?Part 1

Prof

. Jos

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Kritz

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Uni

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Question

Which of these must be scientifically proven for a drug

to be approved by the FDA? (indicate all that apply)

safety in humans

effectiveness for a specific disease compared to

current treatment

ability to synthesize the drug from scratch

clear understanding of how the drug works

Prof

. Jos

hua

Kritz

er, T

ufts

Uni

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Answer

ability to synthesize the drug from scratch

clear understanding of how the drug works

Which of these must be scientifically proven for a drug

to be approved by the FDA? (indicate all that apply)

Prof

. Jos

hua

Kritz

er, T

ufts

Uni

vers

ity

How do drugs work?

Corpora non agunt nisi fixata“an agent cannot act without binding” – Paul Ehrlich, 1913

drug

response

receptor

signaltransduction

cell

Prof

. Jos

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E + S ES E + P

Competitive inhibition

Prof

. Jos

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Kritz

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+I

EI

E + S ES E + P

Competitive inhibition

X X

Prof

. Jos

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ufts

Uni

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Howard Terpning, 1983“Medicine Man of the Cheyenne”

History of Drug Discovery

Page from Dioscorides’ Materia Medica,c. 1334 in Arabic

Ecclesiastes 38:4 The Lord hath created medicines out of the earth; and he that is wise will not abhor them.

Prof

. Jos

hua

Kritz

er, T

ufts

Uni

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Medicine from nature

Willow bark

AspirinAnalgesic since ancient timesChemical isolation of salicin: 1828Chemical synthesis of aspirin: 1853Robust synthesis of aspirin: 1897

Acetylsalicylic acid(Aspirin)

Salicylic acidSalicin

Prof

. Jos

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ufts

Uni

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Natural products

Seed pods of poppies

Cinchona bark

QuinineAnti-malarial since 1630’sChemical isolation: 1820

First chemical synthesis: 1944

MorphineAnalgesic since ancient times

Chemical isolation: 1804First chemical synthesis: 1952

DigitalisHeart rate/blood pressure medication

since late 1700’sChemical isolation: 1875

First chemical synthesis: 1985

Foxgloveleaves

Prof

. Jos

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Kritz

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ufts

Uni

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Question

Which of these must be documented for a dietary supplement to be

allowed by the FDA?(indicate all that apply)

safety in humans

effectiveness for a specific disease or condition

a list of all known bioactive substances in the

supplement

description of known effects on human

physiology

Prof

. Jos

hua

Kritz

er, T

ufts

Uni

vers

ity

Answer

Which of these must be documented for a dietary supplement to be

allowed by the FDA?(indicate all that apply)

safety in humans

effectiveness for a specific disease or condition

a list of all known bioactive substances in the

supplement

description of known effects on human

physiology

none of these

Prof

. Jos

hua

Kritz

er, T

ufts

Uni

vers

ity

Modern drug discovery

1. Find new, useful molecules

2. Test them for efficacy/safety

3. Manufacture them for sale

Prof

. Jos

hua

Kritz

er, T

ufts

Uni

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A drug industry: engineering miracles

Screening, testing, production

1910 – Paul Ehrlich performs the first deliberate screen for a chemical therapy

1928 – Alexander Fleming’s moldy plates1939 – Florey and Chain investigate penicillin, scale

up production1943 – Selman Waksman at Merck discovers

streptomycin from screening soil bacteria1944 – Scale-up of penicillin production1948-1949 – Industrial production of cortisone

Max TishlerB.S. Chemistry, Tufts College

1928, magna cum laude

Prof

. Jos

hua

Kritz

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ufts

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Natural products

High-throughput screening

Structure-based design

Biopharmaceuticals

Genetic therapies

Methods of Drug DiscoveryPart 2

Prof

. Jos

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Natural products success story

PaclitaxelCancer chemotherapy

discovered in 1967Chemical isolation: 1967

First chemical synthesis: 1994

TaxolTM

Taxol acted in a completely unanticipated way, by blocking microtubule formation. Scientists have used Taxol to understand

important aspects of cellular structure and cell division.

Prof

. Jos

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High-throughput screening

Chemical compounds are arrayed in plates with hundreds of tiny, individual wells.

Robots systematically test them in a cell-based tests,or in tests using purified protein targets.

High-Throughput Screening Center Institute for Molecular Medicine FinlandFIMM Nordic EMBL Partnership for Molecular Medicine University of Helsinki

https://www.youtube.com/watch?v=wigd24csyxA

GleevecTM

5/28/2001

Screening success story:

Prof

. Jos

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Structure-based drug design

HIV protease inhibitors

NO

ONH2

HNO

N

HO

N

O N

Starting with its natural substrate,chemists designed and re-designed inhibitors until

they got the desired safety and efficacy.

They used the atom-by-atom 3D structure of HIV protease to guide their designs.

saquinivirnatural HIV protease substrate

Success story:

Prof

. Jos

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Uni

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Biopharmaceuticals

Advantages:Some, like insulin,

are identical to natural molecules in the body

Antibodies (like HerceptinTM) can be developed

to target almosy any protein

DigitalisMW = 781

AspirinMW = 180

InsulinMW = 5808

Disadvantages:Difficult to synthesize – must be

produced from biological sourcesMost cannot be taken orally, and most do not last long in the body

Are usually limited to targetson the outside of the cell

by contrast to “small molecule” drugs, biopharmaceuticals are much larger and more chemically complex.

Prof

. Jos

hua

Kritz

er, T

ufts

Uni

vers

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Genetic therapy: from bench to bedside?

Gene therapies use viruses to deliver missing or broken genes.early failures, but some very recent successes

Nucleic acid drugs can turn on or off certain disease-causing genes.possible “n=1” therapies?

CRISPR gene editing can permanently change the genome itselfrequires further advances in biomolecule delivery

side effects not fully evaluated yet

DNA

genome

RNA

what genes are “on” or

“off” in a cell

protein

biological change

→ →

→ →Almost all current drugs act here…

…but new biotechnology promises to act at the genetic level.

Prof

. Jos

hua

Kritz

er, T

ufts

Uni

vers

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Current Challenges in Drug Discovery

Part 3

1. Find new, useful molecules

2. Test them for efficacy/safety

3. Manufacture them for sale

Prof

. Jos

hua

Kritz

er, T

ufts

Uni

vers

ity

Question

Which single step is the most difficult/limiting stepfor modern drug development?

find new and useful molecules

patent and regulatory costs

large-scale synthesisand purification

testing drugs in humans

Prof

. Jos

hua

Kritz

er, T

ufts

Uni

vers

ity

Answer

Which single step is the most difficult/limiting stepfor modern drug development?

find new and useful molecules

patent and regulatory costs

large-scale synthesisand purification

Prof

. Jos

hua

Kritz

er, T

ufts

Uni

vers

ity

The drug discovery process

Prof

. Jos

hua

Kritz

er, T

ufts

Uni

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Q: Why is drug discovery so difficult?

Prof

. Jos

hua

Kritz

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Uni

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Metabolism

Prof

. Jos

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Kritz

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Uni

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Is target-oriented better?Growth signaling

Prof

. Jos

hua

Kritz

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ufts

Uni

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Q: Why is drug discovery so difficult?

A: We know very little about biology!

Prof

. Jos

hua

Kritz

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ufts

Uni

vers

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Open questions in drug discovery

Currently, we can use our knowledge of biology to choosethe cellular target early on in the drug discovery process.

Is that wise?

Currently, we can directly inhibit onlya small subset of proteins.

Can we target anything in the cell?

Currently, most drugs fail relatively late in clinical trials.

Can we lower this failure rate?

Prof

. Jos

hua

Kritz

er, T

ufts

Uni

vers

ity

Research in the

Developing inhibitors of “undruggable” proteins

Molecules that control autophagy (cellular recycling)

Measuring cell penetration of

biotherapeutics

https://ase.tufts.edu/chemistry/kritzer/kritzerlab1.html

Prof

. Jos

hua

Kritz

er, T

ufts

Uni

vers

ity

Part 1 What are drugs?How drugs work History of drug discovery

Part 2 Methods of drug discoveryNatural productsHigh-throughput screening Structure-based designBiopharmaceuticalsGenetic therapies

Part 3 Current challengesin drug discovery

Introduction to Drug Discovery

Prof

. Jos

hua

Kritz

er, T

ufts

Uni

vers

ity

Learning moreThe Billion-Dollar Molecule: One Company’s Quest for the Perfect Drug and

The Antidote: Inside the World of New Pharma by Barry Werth.

The Poisoner's Handbook: Murder and the Birth of Forensic Medicine in Jazz Age New York, by Deborah Blum.

Her-2: The Making of Herceptin, a Revolutionary Treatment for Breast Cancer by Robert Bazell.

Genentech: The Beginnings of Biotech by Sally Smith Hughes.

The Quest for the Cure: The Science and Stories Behind the Next Generation of Medicines by Brent Stockwell.

Derek Lowe, In the Pipeline, a science-focused blog about the drug industry https://blogs.sciencemag.org/pipeline/

“Forgotten Genius,” a WGBH documentary about Dr. Percy Julian,pioneer African-American medicinal chemisthttp://www.pbs.org/wgbh/nova/julian

Jim Wells and Michelle Arkin, UCSF. “Introduction to Drug Discovery”https://www.youtube.com/watch?v=KQKppAAR3MEhttps://www.youtube.com/watch?v=K9jfvCAPghs

Prof

. Jos

hua

Kritz

er, T

ufts

Uni

vers

ity

Pete

Tur

ner

Thank you!

joshua.kritzer@tufts.edu

@ChemKritzer

https://ase.tufts.edu/chemistry/kritzer/kritzerlab1.html