BMS-986449 is a CELMoD-type molecular gel that remodels the function of regulatory T cells (Treg) and enhances their anti-tumor immune responses by directing the E3 ubiquitin ligase, Cereblon, to target the degradation of IKZF2 (Helios) and IKZF4 (Eos). BMS-986449 has potential application in the study of advanced solid tumors.

BMS-986449 is a CELMoD molecular glue that induces the Cereblon E3 ubiquitin ligase to degrade Treg-specific transcription factors Helios and Eos. BMS-986449 activated primary human Treg cells, led to rapid and deep degradation of Helios and Eos. By day 8 of treatment, the Treg cells exhibited a reprogrammed phenotype characterized by increased expression of effector proteins such as Granzyme B and upregulation of pro-inflammatory gene transcripts, indicating a shift away from an immunosuppressive state[1].

In humanized CRBN knock-in mice, daily oral administration of BMS-986449 induced significant tumor growth inhibition in CT26 (75% TGI), MB49 (62% TGI), and MC38 (42% TGI) models. When combined with anti–PD-1 checkpoint blockade, antitumor efficacy was further enhanced, with TGI values reaching 95%, 97%, and 92%, respectively. In cynomolgus monkeys, daily dosing at 0.1 mg/kg achieved greater than 80% Helios degradation in circulating Treg cells [1].