Abstract 422: A novel potent tetrahydroisoquinoline analog: A cytostatic taxol-like agent.

Abstract In 2024, according to the American Chemical Society, approximately 310,720 new cases of invasive breast cancer will be diagnosed among US women, and 42,250 women will die from breast cancer. Triple-negative breast cancer (TNBC) represents 10 to 15% of all breast cancers. TNBC has fewer treatment options than other types of invasive breast cancer, which limits the effectiveness of targeted hormonal or HER2-directed therapies and is heavily reliant on cytostatic agents such as taxanes and vinca alkaloids. The limited efficacy and increasing side effects of these agents highlight the urgent need for alternative small molecules that block proliferation through novel but less toxic mechanisms. We previously synthesized and characterized tetrahydroisoquinoline (THIQ) derivatives, identifying MG-KKR-4-53 as a highly soluble, non-toxic, and cytostatic agent that halts TNBC cell proliferation without functioning as a spindle poison. Instead, it arrests the cell cycle at G2/M phase. Continuing our research, we further developed a more potent analogue, MG-KRR-5-268, and performed comprehensive in-silico ADMET and cheminformatics analyses, comparing it with Taxol, vinblastine, and MG-KKR-4-53, which map directly to well-known predictive toxicology and metabolism databases/models powered by ADMETlab, SwissADME, and CYP/clearance data. The compounds of interest were synthesized in our lab using O-mesitylene sulfonylhydroxylamine as an aminating agent. Reaction of the Isoquinoliniumamino salt with substituted acid chlorides in anhydrous tetrahydrofuran gave stable ylides. Reduction of the ylides using sodium borohydride gave the target THIQ compounds, which were characterized by NMR and elemental analysis. Compound 3-fluoro-N-(7-hydroxy-3,4-dihydroisoquinolin-2(1H)-yl)-4-methylbenzamide (MG-KKR-5-268) showed significant cytostatic activity with IC50 of 169 nM representing a 7.1-fold increase over MG-KKR-4-53 (IC50 = 1.2 µM). Paclitaxel (250 nM) solidified tumor spheroids at submicromolar concentrations, whereas vinblastine (123nM) caused their disassembly. MG-KRR-5-268 (257nM) exhibited strong prevention of spheroid compaction across submicromolar doses, phenocopying the disassembly of the vinblastine phenotype through a non-tubulin mechanism, compared to the other THIQ analogs. These findings highlighted MG-KRR-5-268 acted as the most potent compound with a novel capacity to prevent 3D tumor solidification through transcriptome reprogramming rather than microtubule binding. Citation Format: Kinfe K. Redda, Madhavi Gangapuram, Suresh Eyunni, Elizabeth Mazzio, Karam F. Soliman. A novel potent tetrahydroisoquinoline analog: A cytostatic taxol-like agent abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 422.