Abstract 5745: Selective anticancer activity and mechanistic insights of novel compounds identified through NCI-60 cancer cell line screening

Targeted cancer therapies aim to maximize efficacy while minimizing side effects. The NCI 60 Human Tumor Cell Line Screen provides a comprehensive platform for identifying compounds with selective anticancer potential across various subtypes. To identify and validate potent anticancer compounds from a 150 compound library, focusing on molecular selectivity, mechanistic insights, and preclinical efficacy. High-throughput screening was performed using the NCI60 platform, followed by cytotoxicity assays (IC50), kinase selectivity profiling, and molecular modeling. Further evaluation utilized 3D spheroid and organoid models, in vivo testing in xenograft models, and mechanistic studies via Western blot to assess apoptosis and pathway modulation. Seventeen compounds (HA45, HA46, HA7, HA12, HA14, HA15, HA16, HA19, HA21, HA23, HA25, HA26, HA64, HA88, HA94, HA96) exhibited significant selectivity, with GI50 values in the nanomolar and micro range. Lead compounds HA45 and HA46 against CNS SNB 74 cell line demonstrated potent kinase inhibition profiles and induced apoptosis through disruption of critical signaling pathways. Molecular docking and dynamics simulations revealed stable interactions with target kinases, corroborating structure-activity relationships. Testing in 3D models confirmed their physiological relevance, and in vivo studies showed tumor growth inhibition with minimal toxicity. This study highlights the utility of integrated methodologies for advancing selective anticancer agents toward clinical application. The findings underscore the importance of combining computational, in vitro, and in vivo approaches in the development of novel cancer therapeutics. Citation Format: Rakaia S. Abdullah, Md Emran Hossain, Eneye David Ajayi, Mostafa M. Aref, Hamed I. Ali. Selective anticancer activity and mechanistic insights of novel compounds identified through NCI-60 cancer cell line screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5745.