Fant Seminar

8/14/2019 Fant Seminar

1/24

Design of Kinase Inhibitorswith Polypharmacological

Modes of Action

Andrew FantUniversity of North Carolina

Eshelman School of PharmacyDivision of Medicinal Chemistry and Natural Products

9 September 2009

Apsel, B. et. al. Targeted Polypharmacology: discovery of dual inhibitors of

tyrosine and phosphoinositide kinases. Nat. Chem. Biol.2008, 4, 691-699


2/24

Cancer in the United States

23.1% of US Deaths in2006 (cdc.gov)

Second-leading cause

in USA War On Cancer since

Nixon in 1971

Full $50M for NC

Cancer Hospital &Linneberger Center

However, not a singledisease http://msnbc.msn.com/id/c3783216


3/24

Hallmarks of Malignancy

Hannahan & Weinberg Cell 1000:57


4/24

Autonomy in Growth Signals

Herbst,R.S et.al. Lung CancerNEJM2008, 359, 13 1367-1380


5/24

Phosphoinositides are Major

Second Messengers EGFR

TrkA Family

IGR

CAM Kinases

RAS

Indirectly regulated byPTEN

Feed AKT and mTOR

Image courtesy of Sigma-Aldrich


6/24

mTOR as a Nexus

Tseng, et al. Drug Discovery Today 12:112


7/24

Why Block TOR in particular?

Shmelze & Hall Cell 103:253


8/24

Kinases as Targets

Pro Primary Regulatory

Mechanism in vivo They can selectively

recognize each other

The ATP binding site

takes a smallmolecule

Con Too Crucial for Life

Processes Specificity in protein-

protein interactions

You really want to

create an ATP-mimetic inhibitor?


9/24

Approved First-Generation

Kinase InhibitorsN

NHN N

HN

NNO

O

N O

N

N

HN

F

Cl

O

OO

OO

HN

N

N

HN

O

S

N

N

N N N

OH

Cl

F

NH

NH

NH

O

N

O

imatininb

gefitinib

erlotinib

dasatinib

sunitinib


10/24

Potential For Overlap?

N

NHN N

HN

N

NO

O

NN

O

HN

HN

O

OHO

OH O

OH

OH

OH

O

O

O O

O

H

OO

O

Bcr-Abl&

c-Kit

PI3 Kinase&

PLK1

multi-proteinkinase

&PI3 Kinases

Apsel, et. al. Nat.Chem. Bio. 4:691


11/24

A Very Distant Relationship

Apsel, et. al. Nat.Chem. Bio.


12/24

Invitrogen High-Throughput

Kinase Assay

http://www.invitrogen.com/site/us/en/home/Products-and-Services/Applications/Drug-Discovery/Target-and-Lead-Identification-and-Validation/KinaseBiology/Kinase-Activity-Assays/Adapta-Universal-Kinase-Assay.html


13/24

Hits

N

N N

N

NH2

OH

S1

N

N N

N

NH2

S2



14/24

Profile



15/24

SAR for Pyrazolopyrimidine

Scaffold

N

N N

N

OP3O10

3-

OHOH

NH2

N

N N

N

R2

NH2 R1

exocyclic amine must be able todonate to a hydrogen bond

R1= naphthyl derivatives favored,

distal substituents OK, especially withH-bond recipients; N in ring helps.

dont come too far off the sides of rings

R2= methyl or isopropyl acceptable, t-butyl kills

activity. 4 or 5 member ring works,especially with heteroatom. Sterochemistry

insensitive

op. cit.: supplementary materials


16/24

Into the Pocket

S1

S2

.



17/24

Conserved Binding Mode

RCSB entry 3ene


18/24

Structural Basis for Selectivity



19/24

Structural Selectivity Redux

Billanges, et. al. Nat. Chem. Bio. 4 648


20/24

PP121 with PI3K and mTOR

N

N N

N

N

NH2

HN

N

O

N

N

N

O

OH



21/24

PP121 with Src and Ret

N

N N

N

N

NH2

HN

N

O

N

N

N

O

OHF

NH

NH

NH

O

N

O



22/24

PP121 Overcomes Mutational

Resistance

N

N N

N

N

NH2

HN

N

O

N

N

N

O

OH

N

NHN N

HN

N

NO



23/24

Conclusions

Kinase Inhibitors arent as selective as oncethought

It is possible to screen libraries of knownKinase Inhibitors for secondary bindingproperties

Proper targeting of polypharmacology allows

mutational resistance to be avoided These techniques do depend on a commonendogenous ligand. Your mileage may vary.


24/24

Acknowledgements

Alex Tropsha

Mike Jarstfer

Adrienne Cox

Tropsha Lab

Warren DeLano/Pymol

Documents

Fant Seminar