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Target-specific inhibition and activation of protein tyrosine phosphatases

Award Number: R15GM071388
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2005
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Target-specific inhibition and activation of protein tyrosine phosphatases - Project Summary The protein tyrosine phosphatases (PTPs), which dephosphorylate specific phosphotyrosine residues in protein substrates, constitute a large family of signaling enzymes, whose activity is ubiquitously misregulated in human diseases. Src-Homology-2-domain- containing PTP 2 (SHP2) represents a striking example of the connection between aberrant PTP activity and pathogenesis, as SHP2 mutations cause the developmental disorders Noonan syndrome and LEOPARD syndrome, and elevated SHP2 activity has been strongly associated with the development of human cancers. Specific Aims 1 and 2 of this proposal describe efforts toward the discovery of selective inhibitors and activators of SHP2 and its disease-associated cysteine mutants, providing direct leads for PTP-directed pharmaceutical development. The proposed experiments of Aim 1 will enable the identification of drug-like compounds that can target SHP2’s unique allosteric site, potentially providing highly selective SHP2 inhibitors. Aim 2 describes small-molecule-discovery efforts targeting two disease-causing SHP2 mutants that contain missense cysteine residues, Y63C and Y279C SHP2, which cause Noonan and LEOPARD syndromes, respectively. Specific Aim 3 presents a strategy for the development of selective, allosteric inhibitors of T-cell protein phosphatase (TCPTP). TCPTP has recently emerged as an intriguing drug target, as disruption of TCPTP activity substantially increases the effectiveness of cancer- fighting immunotherapeutic strategies. However, few TCPTP-directed inhibitor studies have been carried out and no TCPTP-selective allosteric or covalent inhibitors have been previously identified. Although an allosteric-inhibition site on TCPTP is known, the site has only been targeted with low potency, reversible ligands that also inhibit TCPTP’s closest homolog, PTP1B. The proposed work will develop selective covalent TCPTP inhibitors that engage C278—a cysteine residue within TCPTP’s allosteric site that is unique to TCPTP among intracellular PTPs—through rational modification of a known allosteric-site ligand with cysteine- reactive electrophiles. This study will expand the range of PTP-domain cysteines that can be targeted for potent and selective allosteric control of PTP activity and will provide a novel strategy for increasing the efficacy of anti-cancer immunotherapy.


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: 2024 ( Subtotal = $0 )
2024	2021	AMHERST COLLEGE, TRUSTEES OF	155 S PLEASANT ST	AMHERST	MA	01002	HAMPSHIRE	USA	Biomedical Research and Research Training	000	5	8/8/2024	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $411,330 )
2021	2021	AMHERST COLLEGE, TRUSTEES OF	103 CONVERSE HALL	AMHERST	MA	01002	HAMPSHIRE	USA	Biomedical Research and Research Training	001	5	9/10/2021	COMPETING CONTINUATION	$411,330
2021	2016	AMHERST COLLEGE, TRUSTEES OF	155 S PLEASANT ST	AMHERST	MA	01002	HAMPSHIRE	USA	Biomedical Research and Research Training	000	4	1/28/2021	COMPETING CONTINUATION	$0
														Subtotal = $411,330

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2016	AMHERST COLLEGE, TRUSTEES OF	103 CONVERSE HALL	AMHERST	MA	01002	HAMPSHIRE	USA	Biomedical Research and Research Training	001	4	1/5/2017	COMPETING CONTINUATION	$25,978
2017	2012	AMHERST COLLEGE, TRUSTEES OF	103 CONVERSE HALL	AMHERST	MA	01002	HAMPSHIRE	USA	Biomedical Research and Research Training	000	3	1/5/2017	COMPETING CONTINUATION	-$25,978
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $429,337 )
2016	2016	TRUSTEES OF AMHERST COLLEGE	P.O. BOX 5000	AMHERST	MA	01002	HAMPSHIRE	USA	Biomedical Research and Research Training	002	4	7/19/2016	COMPETING CONTINUATION	$429,337
2016	2012	TRUSTEES OF AMHERST COLLEGE	POST OFFICE BOX 5000	AMHERST	MA	010025000	HAMPSHIRE	USA	Biomedical Research and Research Training	001	3	7/14/2016	COMPETING CONTINUATION	$0
2016	2012	TRUSTEES OF AMHERST COLLEGE	POST OFFICE BOX 5000	AMHERST	MA	010025000	HAMPSHIRE	USA	Biomedical Research and Research Training	000	3	5/13/2016	COMPETING CONTINUATION	$0
														Subtotal = $429,337

Issue Date FY: 2012 ( Subtotal = $292,391 )
2012	2012	TRUSTEES OF AMHERST COLLEGE	P.O. BOX 5000	AMHERST	MA	01002	HAMPSHIRE	USA	Biomedical Research and Research Training	000	3	7/31/2012	COMPETING CONTINUATION	$292,391
														Subtotal = $292,391

Issue Date FY: 2009 ( Subtotal = $201,539 )
2009	2009	TRUSTEES OF AMHERST COLLEGE	P.O. BOX 5000	AMHERST	MA	01002	HAMPSHIRE	USA	Biomedical Research and Research Training	000	2	7/20/2009	COMPETING CONTINUATION	$201,539
														Subtotal = $201,539

Issue Date FY: 2005 ( Subtotal = $238,500 )
2005	2005	TRUSTEES OF AMHERST COLLEGE	POST OFFICE BOX 5000	AMHERST	MA	01002	HAMPSHIRE	USA	Biomedical Research and Research Training	000	1	8/22/2005	NEW	$238,500
														Subtotal = $238,500

Grand Total All Awards = $1,573,097

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Target-specific inhibition and activation of protein tyrosine phosphatases

Award Number: R15GM071388

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2005

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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