Abstract LB-295: Discovery of potent selective oral ACSS2 inhibitors for the treatment of acetate avid tumors

• Published in: Cancer research (Chicago, Ill.) Ill.), 2020-08, Vol.80 (16_Supplement), p.LB-295-LB-295
• Main Authors: Goutopoulos, Andreas, Erez, Omri, Nakache, Philippe, Alchanati, Iris, Hay-Koren, Avital, Paz, Dikla, Kovalerchik, Dimitri, Oppenheimer, Hannah, Gottlieb, Eyal, Botti, Simone, Mor, Inbal, Pastukh, Nina
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2020-LB-295

Under the low oxygen and lipid-depleted conditions, often encountered in the tumor microenvironment, acetate is used as nutrient by cancer cells for the biosynthesis of fatty acids. ACSS2, the enzyme responsible for acetate capture within the cell and its conversion into Acetyl-CoA, is upregulated under metabolically stressed conditions and its silencing is shown to inhibit tumor growth in xenografts. Two independent HTS campaigns identified the same small molecule ACSS2 inhibitor series that exhibited uncompetitive binding behavior in respect to ATP. A co-crystal structure of human ACSS2 in complex with a congener of the series revealed that it binds in the acetate pocket and forms favorable interactions with ATP, which is bound adjacently. These compounds were over 1000-fold times selective for ACSS2 over the mitochondrial ACSS1 and other Acyl-CoA synthetases. Medicinal chemistry optimization of this series resulted in advanced compounds with sub-nanomolar biochemical potency and single digit nanomolar cellular EC50s in inhibiting de novo fatty acid synthesis from labeled acetate and excellent pharmacokinetic properties. In vivo, in mice, these compounds inhibited labeling of fatty acids in various tissues after administration of labelled acetate or ethanol. They exhibited in vivo anti-tumor efficacy after oral administration in xenograft models that are acetate avid, whereas had no effect in tumors that show low acetate uptake. MTB-9655, one of the compounds from this series with optimally balanced properties, is currently entering IND-enabling studies to allow its testing in cancer patients. Citation Format: Andreas Goutopoulos, Omri Erez, Philippe Nakache, Iris Alchanati, Avital Hay-Koren, Dikla Paz, Dimitri Kovalerchik, Hannah Oppenheimer, Eyal Gottlieb, Simone Botti, Inbal Mor, Nina Pastukh. Discovery of potent selective oral ACSS2 inhibitors for the treatment of acetate avid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-295.