Wednesday, December 6, 2023 12/6/2023

Chemical Approaches to Cell Signaling Enzymes

Award Number: R01CA074305
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

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Abstract: This longstanding competing renewal application CA74305 concerns our plans to apply chemical and biochemical approaches in cell signaling to enhance our understanding of protein post-translational modifications (PTMs) and the pathways involved. In the next cycle, we plan to investigate the regulation of three key enzymes, PTEN, WWP2, and AKT1 that are connected to the cancer promoting phospholipid, PIP3 (phosphatidyl 3,4,5-triphosphate). PTEN is one of the most commonly mutated tumor suppressor genes and catalyzes the conversion of PIP3 to PIP2 and in this way antagonizes the action of the PI3-kinase oncogenic signaling pathway. WWP2 is a HECT domain E3 ligase (ubiquitin transferase) that targets PTEN for destruction and is considered to be an oncogene. AKT1, also an oncogene, is a protein Ser/Thr kinase that is activated by PIP3 and drives tumor formation and is an intensively studied cancer therapeutic target. PTEN, WWP2, and AKT1 are each subjected to multiple phosphorylations that are proposed to have important regulatory implications. Our research program will continue to adapt and employ protein semisynthetic methods including the newly described enzyme-catalyzed expressed protein ligation (EPL) to generate these signaling enzymes containing the requisite PTMs and appropriate mimics to interrogate how these phosphorylations influence the structure and function of these key cancer-related enzymes. Our three specific aims are: 1. Optimize enzyme-catalyzed expressed protein ligation (EPL) for protein semisynthesis and apply to the study of PTEN regulation; 2. Elucidate the molecular basis of WWP2 E3 ubiquitin ligase regulation; 3. Determine the role of C-terminal phosphorylation of AKT1 on its structure, activity, mechanism of regulation, substrate specificity, and inhibitor sensitivity. With site-specifically modified signaling enzymes in hand, we will integrate kinetic analysis, X-ray crystallography, protein microarrays, and cell-based studies to clarify key regulatory and signaling features. Upon completion of this research effort, we should have a much clearer understanding of the PIP3 signaling network. Moreover, these studies should pave the way for new therapeutic strategies to combat PTEN-AKT1 pathway dysregulation in 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: 2023 ( Subtotal = $382,613 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	001	29	7/17/2023	NON-COMPETING CONTINUATION	$382,613
2023	2022	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	28	1/31/2023	COMPETING CONTINUATION	$0


Issue Date FY: 2022 ( Subtotal = $345,002 )
2022	2022	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	002	28	9/20/2022	COMPETING CONTINUATION	$0
2022	2022	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	28	8/3/2022	COMPETING CONTINUATION	$345,002
2022	2021	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	001	27	9/20/2022	SUPPLEMENT FOR EXPANSION	$0


Issue Date FY: 2021 ( Subtotal = $351,549 )
2021	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	27	5/28/2021	NON-COMPETING CONTINUATION	$340,100
2021	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	001	27	7/19/2021	SUPPLEMENT FOR EXPANSION	$11,449


Issue Date FY: 2020 ( Subtotal = $425,062 )
2020	2020	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	26	5/15/2020	NON-COMPETING CONTINUATION	$425,062


Issue Date FY: 2019 ( Subtotal = $412,311 )
2019	2019	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	25	5/9/2019	NON-COMPETING CONTINUATION	$329,897
2019	2019	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	001	25	5/20/2019	SUPPLEMENT FOR EXPANSION	$82,414


Issue Date FY: 2018 ( Subtotal = $413,613 )
2018	2018	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	004	24	4/30/2018	NON-COMPETING CONTINUATION	$340,100
2018	2018	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	007	24	9/17/2018	SUPPLEMENT FOR EXPANSION	$73,513
2018	2017	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	005	22	5/16/2018	COMPETING CONTINUATION	-$12,312
2018	2017	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	006	23	5/16/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$12,312
2018	2017	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	002	22	4/13/2018	COMPETING CONTINUATION	$21,981
2018	2017	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	000	22	1/29/2018	COMPETING CONTINUATION	-$203,750
2018	2017	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	003	23	4/13/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$21,981
2018	2017	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	001	23	1/30/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$203,750


Issue Date FY: 2017 ( Subtotal = $310,571 )
2017	2017	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	003	22	8/30/2017	COMPETING CONTINUATION	$12,312
2017	2017	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	001	22	6/9/2017	COMPETING CONTINUATION	$310,571
2017	2016	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	002	21	8/30/2017	EXTENSION WITH OR WITHOUT FUNDS	-$12,312
2017	2016	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	000	21	6/6/2017	EXTENSION WITH OR WITHOUT FUNDS	$0


Issue Date FY: 2016 ( Subtotal = $278,598 )
2016	2016	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	000	21	4/8/2016	EXTENSION WITH OR WITHOUT FUNDS	$278,598


Issue Date FY: 2015 ( Subtotal = $278,598 )
2015	2015	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	000	20	4/9/2015	NON-COMPETING CONTINUATION	$278,598


Issue Date FY: 2014 ( Subtotal = $270,240 )
2014	2014	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	000	19	4/9/2014	NON-COMPETING CONTINUATION	$270,240


Issue Date FY: 2013 ( Subtotal = $261,883 )
2013	2013	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	001	18	6/20/2013	NON-COMPETING CONTINUATION	$196,412
2013	2013	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	000	18	5/2/2013	NON-COMPETING CONTINUATION	$65,471


Issue Date FY: 2012 ( Subtotal = $278,598 )
2012	2012	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	000	17	6/21/2012	COMPETING CONTINUATION	$278,598
2012	2011	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	001	16	6/21/2012	NON-COMPETING CONTINUATION	$0


Issue Date FY: 2011 ( Subtotal = $282,037 )
2011	2011	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	001	16	5/17/2011	NON-COMPETING CONTINUATION	$20,352
2011	2011	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	000	16	2/4/2011	NON-COMPETING CONTINUATION	$261,685
2011	2011	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	002	16	5/31/2011	NON-COMPETING CONTINUATION	$0


Issue Date FY: 2010 ( Subtotal = $290,761 )
2010	2010	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	000	15	2/18/2010	NON-COMPETING CONTINUATION	$290,761


Issue Date FY: 2009 ( Subtotal = $290,761 )
2009	2009	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	000	14	2/3/2009	NON-COMPETING CONTINUATION	$261,685
2009	2009	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	001	14	3/17/2009	NON-COMPETING CONTINUATION	$29,076


Grand Total All Awards = $6,901,808

Sum of Action Amount is $6,901,808;

Grand Total = $6,901,808

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Chemical Approaches to Cell Signaling Enzymes

Award Number: R01CA074305

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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