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Identifying primary targets of bumped kinase inhibitor derived compounds to improve utility as therapy for castration resistant prostate cancer

Award Number: R21CA255830
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract Castration-resistant prostate cancer (CRPC) that inevitably escapes primary therapies most often retains dependency on androgen receptor (AR). We are repositioning bumped kinase inhibitors (BKIs), originally designed to inhibit Toxoplasma gondii and Cryptosporidium parvum. A class of BKI-derived compounds (BKIDCs) target lethal CRPC by blocking androgen receptor (AR) signaling, placing AR positive CRPC cells in G1 cell cycle arrest to block their proliferation, and inhibiting glycolysis-derived ATP production. Moreover, our safety and pharmacokinetics data indicate that BKIDCs are compounds that can be reasonably developed as a drug for the treatment of CRPC. Importantly, structure–activity relationship studies revealed that BKIDCs appear to exhibit their antiproliferative activities in prostate cancer through off-target effects (not necessarily as kinase inhibitors), which warrants further investigation of their mechanism of action (MOA). In this proposal we will determine the primary sites of BKIDCs’ action in AR-positive prostate cancer cell lines through both hypothesis-driven and unbiased “-Omics” approaches. We will further validate and characterize potential targets by pharmacological and genetic manipulation. By completing the proposed studies, we will learn MOA of BKIDCs and be ready to take further steps to bring BKIDCs to clinic.


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	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Treatment Research	000	2	1/23/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $242,590 )
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Treatment Research	000	2	1/18/2022	NON-COMPETING CONTINUATION	$222,786
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Treatment Research	001	2	5/17/2022	NON-COMPETING CONTINUATION	$19,804
														Subtotal = $242,590

Issue Date FY: 2021 ( Subtotal = $206,284 )
2021	2021	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Treatment Research	000	1	12/10/2020	NEW	$206,284
														Subtotal = $206,284

Grand Total All Awards = $448,874

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Identifying primary targets of bumped kinase inhibitor derived compounds to improve utility as therapy for castration resistant prostate cancer

Award Number: R21CA255830

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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