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Discovery of novel small molecules targeting a circadian regulatory complex for cancer therapeutics

Award Number: R01CA308442
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/09/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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Discovery of novel small molecules targeting a circadian regulatory complex for cancer therapeutics - Project Summary/Abstract Circadian rhythms are ~24-hour endogenous cycles observed across diverse biological processes. Altered circadian rhythms have been shown to be associated with various diseases, including cancer. Accumulating evidence has demonstrated that the core circadian components, particularly Brain and Muscle ARNT-Like Protein 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK), play important roles in different types of cancer, such as glioblastoma (GBM), acute myeloid leukemia (AML), and hepatocellular carcinoma (HCC). These discoveries underline circadian clocks as a promising novel target for cancer treatment. Currently, however, effective BMAL1- and CLOCK-specific chemical probes are still lacking, which prevents the development of novel cancer therapies that directly target the central clock. To discover small-molecule compounds that can specifically modulate BMAL1:CLOCK and have anti-cancer efficacy, we introduced a new strategy by targeting BMAL1:CLOCK in the context of a holoprotein complex that reflects their native conformation. We developed and validated a new drug discovery pipeline that consists of an affinity selection mass spectrometry (AS-MS) based binding assay combined with a series of cell-based HiBiT reporter assays that can assess the endogenous protein properties and dynamics for hit validation. We have implemented this new pipeline in a small-scale pilot screen and identified two small molecules that selectively target BMAL1 and CLOCK, respectively. In this proposal, we aim to implement our new platform in a large-scale high-throughput screening (HTS) campaign, followed by rigorous hit validation. Meanwhile, we will integrate advanced cheminformatics analysis and medicinal chemistry inspection to prioritize the hit set, as a prelude to understanding structure-activity relationships, and optimization of chosen leads. The success of this project will discover more potent compounds for BMAL1 and CLOCK, which will open the door for novel cancer drug development by targeting the circadian system.


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 = $680,452 )
2026	2026	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Cancer Treatment Research	000	1	6/9/2026	NEW	$680,452
														Subtotal = $680,452

Grand Total All Awards = $680,452

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Discovery of novel small molecules targeting a circadian regulatory complex for cancer therapeutics

Award Number: R01CA308442

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/09/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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