Abstract 5465: Discovery of LXRβ selective agonists promote immune cell activation and induce tumor growth inhibition in syngeneic tumor model

Nuclear receptors, liver X receptor-α (LXRα) and liver X receptor-β (LXRβ), are considered master regulators of lipid homeostasis and play pivotal roles in several physiological and pathological processes ranging from energy supply, cardiovascular, immunity, neurodegenerative disorders and cancer. Therapeutic agonism of the LXR/ApoE axis has proven to promote anti-tumor immunity by targeting immunosuppressive innate immune cells.1 LXR-ApoE pathway regulate the innate immune system in cancer, via modulation of the activity and abundance of myeloid derived suppressor cells (MDSC) and DCs. ApoE binds to Lipoprotein receptor-related protein (LRP) on MDSC induces apoptosis, thus resulting in immune-mediated anti-tumor activity of LXR agonists. Development of LXR agonists as therapeutics has proven quite challenging due to their precipitation of hepatic steatosis and hypertriglyceridemia. Most of the lipogenic effects of LXR agonists are mediated through LXRα.2 LXR subtype-specific agonists (LXRβ specific), may overcome hepatic triglyceride accumulation and (transient) hypertriglyceridemia. Here we report the discovery of IBS624 which is the most selective LXR agonist till date, >185X selective for LXRβ over LXRα. IBS-624 has reasonable exposure in mouse with 40% oral bioavailability. IBS-624 was well tolerated at 100mg/kg, BID for 14 days with no increase in triglycerides and neutropenia. IBS-624 has shown efficacy in MC38 colon cancer model as single agent as well as in combination with Checkpoint inhibitor. 1. Cell. 2018, 172(4): 825-840. 2. Biochemical pharmacology 2006, 71, 453-463 Citation Format: Brahmam Pujala, Balaji Dashrath Sathe, Ashu Gupta, Abhinandan Danodia, Sanjeev Soni, Vivek Kumar, Uzma Saeed, Sarvajit Chakravarty. Discovery of LXRβ selective agonists promote immune cell activation and induce tumor growth inhibition in syngeneic tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5465.