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Novel pan-RAS Inhibitors from Natural Products: A Safer Approach for Colorectal Cancer Interception

Award Number: UG3CA311486
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/09/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Novel pan-RAS Inhibitors from Natural Products: A Safer Approach for Colorectal Cancer Interception - Natural product (NP) libraries offer chemical diversity, providing a valuable resource for drug discovery, especially for challenging targets. NPs have been safely used for centuries, with some having unique target-directed anticancer activity. Leveraging this untapped potential, we propose an innovative assay for high-throughput screening (HTS) of the NCI NP library and follow-up assays to develop a pan-RAS inhibitor for the interception of colorectal cancer (CRC). RAS mutations drive ~30% of cancers and up to 50% of CRC cases, promoting tumor initiation and progression. RAS is an ideal target for CRC interception because of its central role in driving adenoma-adenocarcinoma progression. While FDA-approved mutant-specific KRAS inhibitors have shown therapeutic promise, their utility for prevention is limited due to the heterogeneity of KRAS mutations and compensatory signaling from non-mutant RAS isoforms. A transformative approach would be the development of a pan-RAS inhibitor that selectively eliminates premalignant adenoma cells harboring mutant or activated RAS, thereby blocking CRC at its earliest stage. Our strategy integrates cutting-edge phenotypic screening with advanced analytical and computational tools. We will deploy a cell-based HTS platform using isogenic CRC cell lines that differ only by RAS mutation status to identify compounds with selective antiproliferative activity. Purified compounds provided by NCATS following sub-fractionation of active fractions will be prioritized through secondary assays that assess RAS pathway inhibition and apoptosis induction in mutant KRAS human colon adenoma cells vs. normal colonocytes, enabling ranking of active compounds based on potency and selectivity indices. Affinity selection mass spectrometry (AS-MS) using recombinant RAS proteins, coupled with nucleotide exchange assays, machine learning, and molecular modeling, will rank active compounds based on their capacity to directly bind RAS and inhibit GTP-activation of RAS. Promising leads will be evaluated for drug-like properties, oral bioavailability, and safety through PK/PD studies in mice. Efficacy and target selectivity will be evaluated using a mouse model of KRAS-driven CRC using RAS-specific biomarkers. Animal studies are essential for assessing whole-body effects and safety that cannot be replicated using in vitro models alone. These studies are a critical step in determining whether the approach is suitable for clinical trials. Specific aims are as follows: UG3-1. Develop a phenotypic cell-based HTS assay to identify NP with RAS-selective antiproliferative activity; UG3-2. Develop secondary assays to confirm RAS selectivity and prioritize direct-acting panRAS inhibitors; and UG3-3. Screen the NCI NP library to identify fractions that selectively inhibit RAS-dependent CRC cell proliferation and isolate active compounds. UH3-1. Profiling of purified compounds using secondary and orthogonal assays; UH3-2. Evaluate PK/PD, tolerance, target selectivity, and efficacy in mice. The aims are structured to identify, validate, and advance a novel pan-RAS inhibitor to clinical trials involving individuals with polyposis syndromes at high risk of developing CRC.


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 = $317,704 )
2026	2026	AUBURN UNIVERSITY	321-A INGRAM HALL	AUBURN	AL	36849	LEE	USA	Cancer Cause and Prevention Research	000	1	7/14/2026	NEW	$317,704
														Subtotal = $317,704

Grand Total All Awards = $317,704

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Novel pan-RAS Inhibitors from Natural Products: A Safer Approach for Colorectal Cancer Interception

Award Number: UG3CA311486

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 07/09/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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