Abstract 4215: Targeting TNBC with a novel vorinostat conjugate that selectively inhibits and degrades HDAC3 and HDAC6

Abstract Triple-negative breast cancer (TNBC) once metastatic is often a fatal disease with few molecular targets. HDAC3 is highly expressed in TNBC and regulates metastatic and cell death genes. The clinically approved pan-HDAC inhibitors exhibit limited efficacy with side effects in clinical trials. We have reported that the semisynthetic 18β-glycyrrhetinic acid analogues (10a-10e) bearing the 1-en-2-cyano-3-oxo substitution degrade HDAC3/6 proteins without direct enzymatic inhibition. We constructed AH3 to produce both HDAC 3/6 degradation and enzyme activity inhibition by 10a conjugation with the HDAC inhibitor vorinostat. AH3 has increased selectivity to HDAC3 and HDAC6 inhibition as compared to vorinostat. TNBC (MDA-MB-321, MDA-MB-468 and BT-459 cells) are more growth inhibited by AH3 (GI50:0.6-1 μM) comparing to vorinostat (GI50:1.9-2.9 μM) and exhibits selectivity for TNBC compared to normal mammary epithelial cells. Modification of the hydroxamic acid of AH3 with a methyl group (AH3-OCH3) loses HDAC inhibition and cell growth inhibition, confirming that HDAC3 and HDAC6 are the targets of AH3. AH3 inhibits colony formation, cellular invasion and migration in TNBC cells. AH3, but not AH3-OCH, induces apoptosis with downregulation of c-FLIP and upregulation of NOXA, associated with upregulation of acetyl-H3 and acetyl-tubulin as well as down-regulation of HDAC3 and HDAC6 proteins. AH3 has better tumor growth inhibition ability than verinostat in MDA-MB-231 xenograft model. AH3 is novel since both degrades and acts as an HDAC3/HDAC6 selective inhibitor with enhanced selectivity and antitumor ability against TNBC. Citation Format: Ping Gong, Min Huang, Haoling Wang, Xin Li, Linxiang Zhao, Samuel Waxman, Yongkui Jing. Targeting TNBC with a novel vorinostat conjugate that selectively inhibits and degrades HDAC3 and HDAC6 [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 4215.