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Mcl-1/Bfl-1 in apoptosis and signal transduction: a structure/function approach

Award Number: R01CA168517
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/09/2012
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Mcl-1/Bfl-1 in apoptosis and signal transduction: a structure/function approach - PROJECT SUMMARY Given the pivotal role of anti-apoptotic Bcl-2 family of proteins in cancer cell survival and resistance to chemotherapy, the development of novel anti-cancer therapeutics targeting the BH3 binding groove of anti- apoptotic Bcl-2 proteins have emerged as a promising, yet challenging therapeutic goal. The recent approval of Venetoclax (ABT199), a selective Bcl-2 antagonist whose design and development spanned well over fifteen years of iterative optimizations using extensive structure-based refinements, suggested that it is indeed possible, albeit extremely challenging, to attain inhibitors of protein-protein interactions (PPIs) that are clinically relevant. However, we and others found that overexpression of both Mcl-1 and, perhaps more relevant, Bfl-1 (two other members of the Bcl-2 family protein that are not targeted by Venetoclax), confer resistance to chemotherapy and to Bcl-2 antagonists. Recent efforts from our laboratory identified possible novel routes to design potent and selective inhibitors of PPIs targeting these oncogenes that encompass structure-based design of covalent inhibitors. Hence, we propose to further investigate these innovative structure-guided drug discovery strategies and to apply them to the design of potent dual Mcl-1/Bfl-1 antagonists. If successful, our studies could result in general methods to target PPIs and could also identify innovative lead compounds for the treatment of cancer.


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: 2026 ( Subtotal = $0 )
2026	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Cancer Treatment Research	000	10	12/8/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $411,639 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Cancer Treatment Research	001	10	4/17/2024	NON-COMPETING CONTINUATION	$21,665
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Cancer Treatment Research	000	10	11/3/2023	NON-COMPETING CONTINUATION	$389,974
														Subtotal = $411,639

Issue Date FY: 2023 ( Subtotal = $424,639 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Cancer Treatment Research	001	9	3/15/2023	NON-COMPETING CONTINUATION	$34,665
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Cancer Treatment Research	000	9	11/10/2022	NON-COMPETING CONTINUATION	$389,974
														Subtotal = $424,639

Issue Date FY: 2022 ( Subtotal = $424,639 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	900 UNIVERSITY AVE	RIVERSIDE	CA	92521	RIVERSIDE	USA	Cancer Treatment Research	000	8	11/4/2021	NON-COMPETING CONTINUATION	$389,973
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	900 UNIVERSITY AVE	RIVERSIDE	CA	92521	RIVERSIDE	USA	Cancer Treatment Research	001	8	5/6/2022	NON-COMPETING CONTINUATION	$34,666
														Subtotal = $424,639

Issue Date FY: 2021 ( Subtotal = $433,304 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFFICE BLDG	RIVERSIDE	CA	92521	RIVERSIDE	USA	Cancer Treatment Research	001	7	1/22/2021	NON-COMPETING CONTINUATION	$21,666
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFFICE BLDG	RIVERSIDE	CA	92521	RIVERSIDE	USA	Cancer Treatment Research	000	7	11/16/2020	NON-COMPETING CONTINUATION	$411,638
														Subtotal = $433,304

Issue Date FY: 2020 ( Subtotal = $433,304 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFFICE BLDG	RIVERSIDE	CA	92521	RIVERSIDE	USA	Cancer Treatment Research	000	6	12/12/2019	COMPETING CONTINUATION	$433,304
														Subtotal = $433,304

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2016	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFFICE BLDG	RIVERSIDE	CA	92521	RIVERSIDE	USA	Cancer Treatment Research	000	5	8/14/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2016	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFFICE BLDG	RIVERSIDE	CA	92521	RIVERSIDE	USA	Cancer Treatment Research	000	5	2/14/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $474,252 )
2016	2016	REGENTS, UNIVERSITY OF CALIFORNIA	POST OFFICE BOX 112	RIVERSIDE	CA	92521	RIVERSIDE	USA	Cancer Treatment Research	001	5	7/5/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$474,252
2016	2015	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Treatment Research	000	4	7/1/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $474,252

Issue Date FY: 2015 ( Subtotal = $521,604 )
2015	2015	SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Treatment Research	000	4	4/27/2015	NON-COMPETING CONTINUATION	$521,604
														Subtotal = $521,604

Issue Date FY: 2014 ( Subtotal = $505,956 )
2014	2014	SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Treatment Research	000	3	4/25/2014	NON-COMPETING CONTINUATION	$505,956
														Subtotal = $505,956

Issue Date FY: 2013 ( Subtotal = $490,308 )
2013	2013	SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Treatment Research	001	2	7/2/2013	NON-COMPETING CONTINUATION	$367,731
2013	2013	SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Treatment Research	000	2	5/7/2013	NON-COMPETING CONTINUATION	$122,577
														Subtotal = $490,308

Issue Date FY: 2012 ( Subtotal = $545,354 )
2012	2012	SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Treatment Research	000	1	7/9/2012	NEW	$545,354
														Subtotal = $545,354

Grand Total All Awards = $4,664,999

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Mcl-1/Bfl-1 in apoptosis and signal transduction: a structure/function approach

Award Number: R01CA168517

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/09/2012

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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