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BIMODAL PTP-1B INHIBITORS USING TETHERING TECHNOLOGY

Award Number: R43DK063764
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2003
PERIOD OF PERFORMANCE END DATE: 02/28/2005

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BIMODAL PTP-1B INHIBITORS USING TETHERING TECHNOLOGY - DESCRIPTION (provided by applicant): The long-term objective of this proposal is to apply a powerful "covalent tethering" technology to discover novel therapeutics for the treatment of type 2 diabetes. Protein tyrosine phosphatase-1B (PTP-1B) has emerged as a compelling target for treating diabetes, but it has been difficult to identify cell permeable, drug-like inhibitors of this important enzyme. Covalent tethering technology involves discovering drug-like fragments that bind to a target protein and assembling them into potent inhibitors. Cysteine mutations are introduced to target a site of interest and a collection of disulfide-containing fragments are screened to identify compounds that bind and form a disulfide bond. Compared to traditional screening, a greater chemical diversity is surveyed by identifying the individual components of binding and subsequently combining them into a common molecule. We propose to use covalent tethering and structure-based design to target two adjacent binding sites on PTP-1B. We will first identify pharmaceutically desirable phophotyrosine mimetics for the conserved active site and then identify fragments that bind to a unique, nearby site. These fragments will be merged into a bimodal inhibitor that combines potency and specificity to overcome problems observed with existing inhibitors. Covalent tethering is ideally suited to identifying such bimodal molecules.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2004 ( Subtotal = $250,000 )
2004	2004	SUNESIS PHARMACEUTICALS	3696 HAVEN AVENUE SUITE C	REDWOOD CITY	CA	94063	SAN MATEO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/26/2004	NON-COMPETING CONTINUATION	$250,000
														Subtotal = $250,000

Issue Date FY: 2003 ( Subtotal = $250,000 )
2003	2003	SUNESIS PHARMACEUTICALS	3696 HAVEN AVENUE SUITE C	REDWOOD CITY	CA	94063	SAN MATEO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1		NEW	$250,000
														Subtotal = $250,000

Grand Total All Awards = $500,000

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BIMODAL PTP-1B INHIBITORS USING TETHERING TECHNOLOGY

Award Number: R43DK063764

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/01/2003

PERIOD OF PERFORMANCE END DATE: 02/28/2005

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