作为强效选择性Helios降解剂的吡啶基苄胺类似物1的鉴定与优化

Small molecule approaches that enhance antitumor immunity have the potential to broaden the benefit of cancer immunotherapy as monotherapies or in combination with immune checkpoint inhibitors (ICIs). Indeed, despite the success of ICIs, resistance and limited response in some patients highlight the need for alternative strategies. FOXP3+ regulatory T (Treg) cells within the tumor microenvironment (TME) suppress antitumor immunity and limit the efficacy of ICIs in some tumor types. Transcriptional reprogramming of Treg cells represents a novel and promising therapeutic approach to treat such patients. IKZF2 (Helios), a zinc finger transcription factor selectively expressed in Treg cells, contributes to the transcriptional immunosuppressive phenotype of these cells, including silencing of IL-2 expression. Genetic deletion of IKZF2 in FOXP3+ cells enhances antitumor responses in preclinical models, establishing it as a nonredundant regulator of Treg cell function. Although transcription factors have traditionally been considered “undruggable,” the discovery of cereblon (CRBN)-mediated degradation of zinc finger proteins by immunomodulatory imide drugs (IMiDs™) has enabled targeted protein degradation (TPD) of factors such as IKZF1 (Ikaros) and IKZF3 (Aiolos). We recently disclosed the discovery of a potent and selective IKZF2 degrader, BMS-986449, derived from lenalidomide/pomalidomide scaffolds. Herein, we report SAR optimization studies leading to the identification of a pyridylbenzylamine appended lenalidomide analog (compound 1) with excellent Helios degradation activity and improved selectivity over related neosubstrates (e.g. IKZF1, IKZF3, and CK1alpha). In addition, ­1 also exhibited favorable ADME properties and robust in vivo pharmacodynamic effects in a mouse syngeneic model.