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Development of Quinoxaline Based IKKbeta Inhibitors for Kras Driven Cancers

Award Number: R01CA197999
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/09/2016
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Development of Quinoxaline Based IKKbeta Inhibitors for Kras Driven Cancers - Project Summary Activation of IKKbeta has been implicated in inflammation and in mouse models accelerates tumorigenesis in the presence of an oncogene or the loss of tumor suppressor gene. Four IKKbeta inhibitors entered clinical trials however none were FDA approved due to unfavorable safety profile, lack of efficacy or portfolio repositioning. MAP3K1 is an upstream kinase that phosphorylates IKKb and higher MAP3K1 levels is associated with poorer 5-year survival in pancreatic cancer patients, making it an attractive therapeutic target. We recently reported the discovery of a MAP3K1 inhibitor (IKAM-1) that reduced p-IKKb levels, reduced tumor growth and metastasis in Krasmutation driven pancreatic cancer. Structure-guided modification validated IKAM-1 binding mode and identified 2 as an improved inhibitor. With 12 proteolysis targeting chimeras (PROTACs) currently in clinical trials PROTACs are rapidly emerging as a mainstream approach in drug discovery. Synthesis and evaluation of a focused set of PROTACs using 2 as the head group led to the identification of 50-008 that exhibited broad anticancer activities with IC50 < 100 nM in 269 cancer cell lines. In this application we propose, to (a) conduct RNA-seq and proteome-wide screens to elucidate the mechanism of action, (b) optimize for efficacy through optimization of linker conformation and (c) evaluate 50-008 or an improved analog in organoids and tumor models. These studies will identify a lead candidate with defined MOA suitable for IND enabling toxicity studies.


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	2025	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	4215 EMILE ST	OMAHA	NE	68105	DOUGLAS	USA	Cancer Treatment Research	000	8	2/23/2026	NON-COMPETING CONTINUATION	-$383,749
2026	2025	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cancer Treatment Research	001	9	2/23/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$383,749
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $383,750 )
2025	2025	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	4215 EMILE ST	OMAHA	NE	68105	DOUGLAS	USA	Cancer Treatment Research	000	8	7/4/2025	NON-COMPETING CONTINUATION	$383,750
														Subtotal = $383,750

Issue Date FY: 2024 ( Subtotal = $364,563 )
2024	2024	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Treatment Research	000	7	6/20/2024	NON-COMPETING CONTINUATION	$364,563
														Subtotal = $364,563

Issue Date FY: 2023 ( Subtotal = $383,750 )
2023	2023	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Treatment Research	000	6	7/5/2023	COMPETING CONTINUATION	$383,750
														Subtotal = $383,750

Issue Date FY: 2022 ( Subtotal = -$316 )
2022	2020	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Treatment Research	000	5	9/21/2022	NON-COMPETING CONTINUATION	-$316
														Subtotal = -$316

Issue Date FY: 2020 ( Subtotal = $344,094 )
2020	2020	UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Treatment Research	000	5	3/26/2020	NON-COMPETING CONTINUATION	$344,094
														Subtotal = $344,094

Issue Date FY: 2019 ( Subtotal = $333,770 )
2019	2019	UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Treatment Research	000	4	4/23/2019	NON-COMPETING CONTINUATION	$333,770
														Subtotal = $333,770

Issue Date FY: 2018 ( Subtotal = $344,094 )
2018	2018	UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Treatment Research	000	3	4/12/2018	NON-COMPETING CONTINUATION	$344,094
														Subtotal = $344,094

Issue Date FY: 2017 ( Subtotal = $344,094 )
2017	2017	UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Treatment Research	001	2	6/7/2017	NON-COMPETING CONTINUATION	$34,410
2017	2017	UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Treatment Research	000	2	4/28/2017	NON-COMPETING CONTINUATION	$309,684
														Subtotal = $344,094

Issue Date FY: 2016 ( Subtotal = $355,646 )
2016	2016	UNIVERSITY OF NEBRASKA MEDICAL CENTER	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Treatment Research	000	1	5/9/2016	NEW	$355,646
														Subtotal = $355,646

Grand Total All Awards = $2,853,445

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Development of Quinoxaline Based IKKbeta Inhibitors for Kras Driven Cancers

Award Number: R01CA197999

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/09/2016

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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