Abstract 3510: Small molecule ACSS2 inhibitors target acetate metabolizing tumor cells in hypoxic conditions

Abstract

Abstract BACKGROUND Tumors such as glioblastoma proliferating under hypoxic, hypoglycemic and hypolipidemic conditions derive almost half of their nutritional requirement from the short chain fatty acid acetate. Acetyl CoA synthetases (ACSS 1 to 3) are a family of enzymes that metabolize acetate to the multifunctional metabolite acetyl-CoA. Acetyl-coA is a key precursor of cellular biomass and is required for epigenetic modification. There is an increasing body of clinical evidence that places acetate and ACSS2 at a critical metabolic node in tumors. We have developed potent small molecule enzyme inhibitors of ACSS2 that block the functional activity of the enzyme in vitro and in vivo. Furthermore, these inhibitors synergize with known chemotherapeutics to eliminate cancer cells in hypoxic conditions. METHODS A pharmacophore based medicinal chemistry campaign yielded initial hits which were refined in subsequent rounds of structure activity relationships. ACSS2 activity was measured in cell free and cellular assays by monitoring the conversion of radiolabelled acetate to biomass in depleted oxygen environments and in combination with chemotherapeutics such as doxorubicin. RESULTS Our medicinal chemistry campaign yielded several highly potent ACSS2 specific enzyme inhibitors with good pharmacokinetic properties in the rodent. Our lead compound CRD1400 is an ACSS2 specific inhibitor with low nanomolar potency and kills acetate dependent tumor cells and sensitizes several tumor cell lines to the chemotherapeutic doxorubicin. CRD1400 is has been selected for further assessment in patient derived xenograft models based on its potency for increased cell killing under hypoxic conditions. CONCLUSIONS Inhibition of the enzyme ACSS2 depletes tumor cells of the nutrient acetate and provides a new modality of attacking metabolic vulnerabilities in tumors. When used in combination, CRD1400 reduces chemotherapeutic resistance that arises in low oxygen environments common in tumors and enhances the potency of commonly used cancer medication. Citation Format: Monali Banerjee, Sourav Basu, Debjani Chakraborty, Ritesh Shrivastava, Sandip Middya, Rajib Ghosh, Dharmendra Yadav, Arghyotri Sinha, Avratanu Das, Navin Pandit, Mohinder Naiya, Sabyasachi Debnath, Sangeeta Dey, Debottam Dasgupta, Nirmal Das, Anuj Singh, Dipayan Sarkar, Sukanya Sarkar, Ganesh Narasipuram, Nagaswami Mane, Nicky Singhal, Nidhi Rawat, Anindita Middya, Arjun Surya. Small molecule ACSS2 inhibitors target acetate metabolizing tumor cells in hypoxic conditions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3510.