Abstract ND05: The discovery of BMS-986449, a highly potent and selective degrader of the transcription factors Helios (IKZF2) and Eos (IKZF4) for the treatment of solid tumors

Abstract Regulatory T (Treg) cell abundance in the tumor microenvironment is associated with poor responses to immunotherapies, such as nivolumab. The transcription factors Helios (IKZF2) and Eos (IKZF4) are abundantly expressed in Treg cells and contribute to the immunosuppressive phenotype associated with this T-cell subset. We and others have postulated that degradation of Helios and Eos could re-polarize Treg cells towards a less suppressive, more inflammatory phenotype that would result in an enhanced antitumor effector T cell response. This presentation will describe the discovery and characterization of BMS-986449, a Cereblon E3 Ligase Modulatory Drug (CELMoD™) molecular glue degrader of Helios and Eos. BMS-986449 is a potent and orally bioavailable degrader of IKZF2/4 with minimal impact on IKZF1/3 levels in regulatory T-cells as assessed by global proteomics. BMS-986449 affects in vitro reprogramming of Treg cells to have a more effector-like phenotype that results in promising in vivo efficacy in syngeneic tumor models. In cynomolgus monkeys, oral administration of BMS-986449 (0.3 mg/kg, QD) was well-tolerated and maintained ≥80% degradation of Helios in circulating Treg cells over 24h. Given the positive outcomes from these pre-clinical studies and an acceptable safety profile, BMS-986449 was advanced into Phase I/II clinical trials for patients with advanced solid tumors. Citation Format: Aaron Balog. The discovery of BMS-986449, a highly potent and selective degrader of the transcription factors Helios (IKZF2) and Eos (IKZF4) for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr ND05.