Version 2.1.1.0

Abstract

Grant Number:	1R43CA103415-01
PI Name:	BREMER, RYAN E.
PI Email:	rbremer@plexxikon.com
PI Title:
Project Title:	Novel Scaffold Discovery for Pim-1 Kinase

Abstract: DESCRIPTION (provided by applicant): Pim-1 is a serine/threonine kinase that has been implicated in the progression of several cancers, including prostate cancer and various leukemias. Using X-ray co-crystallography of small, "scaffold-like" molecules with Pim-1, several new classes of chemical scaffolds that will be the basis for the development of a Pim-1 specific inhibitor will be identified. By focusing on structure and using X-ray co-crystallography as a screen at the earliest stage of lead discovery, it will be possible to directly discover novel scaffolds for Pim-1 that will be the foundation for a potent, selective Pim-1 inhibitor. The structural understanding of the scaffold: protein complex at the outset of the discovery process will be invaluable in identifying key objectives and focusing synthetic chemistry efforts in an efficient manner. The feasibility and utility of scaffold discovery for Pim-1 will be demonstrated by the successful completion of the proposed 20 co-crystal structures and the subsequent improvements in potency and selectivity observed for the 80-100 synthesized compounds. The scaffolds and compounds identified here will be the basis for the eventual identification of a Pim-1 inhibitor as a preclinical candidate for cancer therapy.

Thesaurus Terms:
drug design /synthesis /production, drug discovery /isolation, neoplasm /cancer chemotherapy, protein kinase inhibitor, protooncogene, serine threonine protein kinase
active site, combinatorial chemistry, enzyme structure
X ray crystallography

Institution:	PLEXXIKON, INC.
	91 BOLIVAR DR, STE A
	BERKELEY, CA 94710
Fiscal Year:	2003
Department:
Project Start:	03-JUL-2003
Project End:	30-JUN-2004
ICD:	NATIONAL CANCER INSTITUTE
IRG:	ZRG1

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