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The molecular basis of IMiD induced neo-substrate recruitment to the CRL4CRBN ubiquitin E3 ligase

Award Number: R01CA214608
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2017
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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The molecular basis of IMiD induced neo-substrate recruitment to the CRL4CRBN ubiquitin E3 ligase - Project Summary Developed in the 1950s, Thalidomide was used to treat morning sickness in the early stages of pregnancy, which led to the birth of thousands of children with severe birth defects and subsequent withdrawal from the market. Today, thalidomide and its analogs lenalidomide and pomalidomide (collectively known as IMiDs) are FDA approved drugs and effective treatments for hematologic malignancies such as multiple myeloma and Del(5q) MDS. But despite over 60 years of research, the mechanistic understanding of how these molecules cause the characteristic birth defects is only just beginning to unravel. Due to the wide use of IMiDs in the clinic, and the recent explosion in the development of targeted protein degradation therapies based often on the original thalidomide scaffold, it is more critical than ever that we understand the full range of potential activities that IMiDs provoke. Here, we propose to explore the broad range of potential activities that result from these IMiD-like molecules binding to the E3 ligase CUL4-RBX1-DDB1-CRBN (CRL4CRBN) and redirecting its activity towards different targets. Specifically, in aim 1, we will engineer an in vivo mouse model of Sall4 degradation to dissect how thalidomide-mediated degradation of Sall4 leads to teratogenicity. We will do this through a combination of expression analyses and developmental measurements to assess the affect that IMiD molecules have on the developing embryo. This will not only enable the study of the mechanism of teratogenic activity of these drugs but will also provide a critical model system for testing the toxicity of current and future versions of these molecules. Not only do these molecules induce a gain-of-function to target new proteins, but they also induce a loss-of-function and in aim 2, we propose to use novel mass spectrometry-based proteomics technology in combination with potent and selective tool compounds to explore the biological consequences of blocking CRBN activity. We have previously shown that we can expand the scope of IMiD targets through rational design of new IMiD-like molecules capable of degrading new proteins related to known targets. In aim 3, we propose to expand the target scope even further by developing novel chemistry to target structurally diverse proteins that have a strong therapeutic rationale, thus providing proof-of-concept for target expansion and providing chemical leads for new therapeutic targets. The overarching goal of this grant is to explore the full range of potential activities of the widely utilized CRL4CRBN ligase by identifying and exploring the mechanistic consequences of degrading its physiological and IMiD-induced targets, as well as seeking to expand its target space into currently undruggable territories.


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: 2025 ( Subtotal = $363,568 )
2025	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	000	9	3/20/2025	NON-COMPETING CONTINUATION	$363,568
														Subtotal = $363,568

Issue Date FY: 2024 ( Subtotal = $378,504 )
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	000	8	4/17/2024	NON-COMPETING CONTINUATION	$378,504
														Subtotal = $378,504

Issue Date FY: 2023 ( Subtotal = $388,760 )
2023	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	7	7/14/2023	NON-COMPETING CONTINUATION	$388,760
														Subtotal = $388,760

Issue Date FY: 2022 ( Subtotal = $370,095 )
2022	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	001	6	5/25/2022	COMPETING CONTINUATION	$406,564
2022	2021	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	5	5/12/2022	NON-COMPETING CONTINUATION	-$36,469
														Subtotal = $370,095

Issue Date FY: 2021 ( Subtotal = $395,901 )
2021	2021	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	5	3/19/2021	NON-COMPETING CONTINUATION	$395,901
														Subtotal = $395,901

Issue Date FY: 2020 ( Subtotal = $395,901 )
2020	2020	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	4	1/29/2020	NON-COMPETING CONTINUATION	$395,901
														Subtotal = $395,901

Issue Date FY: 2019 ( Subtotal = $384,023 )
2019	2019	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	3	3/22/2019	NON-COMPETING CONTINUATION	$384,023
														Subtotal = $384,023

Issue Date FY: 2018 ( Subtotal = $410,426 )
2018	2018	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	2	2/13/2018	NON-COMPETING CONTINUATION	$369,383
2018	2018	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	001	2	5/24/2018	NON-COMPETING CONTINUATION	$41,043
														Subtotal = $410,426

Issue Date FY: 2017 ( Subtotal = $426,818 )
2017	2017	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	1	2/28/2017	NEW	$426,818
														Subtotal = $426,818

Grand Total All Awards = $3,513,996

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The molecular basis of IMiD induced neo-substrate recruitment to the CRL4CRBN ubiquitin E3 ligase

Award Number: R01CA214608

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2017

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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