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Discovery and validation of CYP8B1 Inhibitors as probes for targeting Hepatocellular Carcinomas (HCC)

Award Number: R01CA301510
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2025
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Discovery and validation of CYP8B1 Inhibitors as probes for targeting Hepatocellular Carcinomas (HCC) - PROJECT SUMMARY Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. FDA-approved small molecule drugs for the treatment of HCC primarily target kinases within cancer cells. Current treatments for HCC are ineffective and cancer resistance is common while treated individuals obtain only brief survival. The development of cancer involves a complex interplay of various proteins in addition to dysregulation of kinases. There is a significant lag in discovery of small molecules that modulate non-kinase targets for the treatment of HCC. Our long-term goal is to meet the critical unmet need for innovative pharmacological therapies with desirable safety profiles and durable treatment effects for HCC, including metabolic dysfunction associated HCC. Bile acids (BAs) play important roles in regulating metabolism, inflammation, and cancer. CYP8B1 (also known as sterol 12-alpha-hydroxylase), which is exclusively expressed in the liver hepatocytes, functions to specifically control the 12α-hydroxylated (OH)/non-12α-OH BA ratio within the BA pool. CYP8B1 deficiency generates beneficial profiles of BA and gut microbiota, thereby improving systematic metabolism and immunity, suppressing tumorigenesis, as well as inducing apoptosis. Thus, CYP8B1 is a novel and promising therapeutic target for drug discovery to treat HCC. Indeed, rodents with a natural Cyp8b1 gene deletion (such as the naked mole-rat) are cancer resistant, and our preliminary research observed less aggressive tumors in Cyp8b1 KO mice in a rapid HCC model. We hypothesize that CYP8B1-specific inhibitors may provide a unique pharmacological approach to treat HCC. Therefore, the direct objective of this grant proposal is to develop selective small molecule inhibitors against CYP8B1 to treat HCC, including metabolic dysfunction associated HCC. To the best of our knowledge, we are the first group to explore anti-HCC drug discovery targeting a non- kinase target — a CYP family member to develop selective CYP8B1 inhibitors. This proposal is in collaboration with Sanford Burnham Prebys (SBP) Medical Discovery Institute, a well-established, NCI-CBC dedicated center and NCI-designated basic cancer center. The assembled team is well-qualified to complete the following Specific Aims: 1) To identify CYP8B1 inhibitors via HTS of the SBP ~250K compound library; 2) To validate hits for potency, specificity, and rationalize SAR by structural & biophysical studies; and 3) To identify the mode of action (MOA) and biological effects of validated CYP8B1 inhibitor lead candidates on HCC. The completion of the proposed studies will have identified novel, potent, and specific CYP8B1 inhibitors, providing not only a small molecule tool for researching the crucial role of CYP8B1 in cancer (scientific), but also offering prototype lead candidate(s) for developing potential first-in-class pharmaceutical treatment for HCC with translational significance (translational) in follow-up grant 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 = $772,905 )
2026	2026	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	2	4/9/2026	NON-COMPETING CONTINUATION	$772,905
														Subtotal = $772,905

Issue Date FY: 2025 ( Subtotal = $793,324 )
2025	2025	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	1	4/11/2025	NEW	$793,324
														Subtotal = $793,324

Grand Total All Awards = $1,566,229

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Discovery and validation of CYP8B1 Inhibitors as probes for targeting Hepatocellular Carcinomas (HCC)

Award Number: R01CA301510

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/15/2025

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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