Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements.

OCH3

NO

OHO O

HOO

O

OH

O

OCH3

H3COO

Natural Products lead to Unanticipated Drug Targets and Mechanisms

FKBP bindingdomain

mTOR effectordomain

Sehgal, S.N.; Baker, H.; Vézina, C., J. Antibiot., 1975, 28(10), 721-726.Choi, J.; Chen, J.; Schrieber, S.L.; Clardy, J., Science, 1996, 273, 239-241.

1. Rapamycin binds tightly to FKPB12 via FKBP binding domain2. Rapa-FKBP12 complex binds mTOR, disrupting TORC1 complex

mTOR

FKBP-12

RAPAMYCIN

1

Natural products, by virtue their origin, are within or at least proximal to, biologically relevant chemical space!

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements.

ILS-920 Promotes Neurite Outgrowth and Neuronal Survival in Cortical Neuron Cultures

Control ILS-920

Control ILS-920

0.5

1

1.5

2

2.5

3

Ne

uro

fila

me

nt

Co

nte

nt

(OD

@ 6

50

nm

)

ILS-920

Ruan, B. et. al. “Binding of rapamycin analogs to calcium channels and FKBP52 contributes to their neuroprotective activities” (2008) Proc. Natl. Acad. Sci. USA, 105(1), 33-38.

O

N

O

OHO O

OOH

O

O

O

OH

O

O

O N

OMe

N

O

OHO O

OH

O

O

OR

O

OMe

MeOO

ILS-920

rapamycin

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements.

Varenicline

NN

H

NH

N

NH

N

N

nicotineNicotiana tabacum

cytisineLupinus sp.

Plant Natural Products as Drug Leads- Varenicline

VareniclineHomo sapiens

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements.

4

Summary

n Natural products have been, and continue to be a rich source of chemotherapeutics

n Natural products are biologically privileged chemical structures with which to attack previously undruggable targets.

n Natural products are biologically privileged structures which can be leveraged for new biology and targets.

n Complex natural products can access desired drug property space

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements.

Acknowledgments

Natural Products/Chemistry Neuroscience/Biology

Benfang Ruan Kevin Pong

Edmund Graziani Mene Pangelos

Leonard McDonald Flora Jow,

Ronald L. Magolda Andrew Wood

Guy Carter Mark Bowlby

Jerauld Skotnicki Peter H. Reinhart

Magid Abou-Gharbia Margaret M. Zaleska

Xidong Feng Danni Liu

Caroline Proul-LaFrance Shi Liang

Jack Bikker Robert A. Crozier

Bruce Rogers Mary Lynn Mercado

Anabella Villalobos Jotham Coe

Brian O’neill David von Schack

Jotham Coe Yi Chen