Discovery of a selective CDK7 PROTAC against acute leukemia with low platelet toxicity

Abstract

Cyclin-dependent kinase 7 (CDK7), a key regulator of cell cycle progression and transcriptional control, has emerged as a promising therapeutic target in acute leukemia. While CDK7 inhibitors have shown antileukemic activity, their clinical utility is often restricted by dose-dependent thrombocytopenia. To overcome this challenge, we developed and characterized a series of CDK7-selective PROTAC degraders. By engaging the VHL E3 ligase, which is minimally expressed in platelets, CXJ2080 achieves tumor-selective CDK7 degradation with remarkable potency and selectivity (a DC₅₀ of 0.88 nM and >98% degradation efficiency). This selective targeting spares platelets, thereby avoiding the hematologic toxicity associated with conventional CDK7 inhibitors. Mechanistically, CDK7 degradation disrupts the CDK7-cyclin H-MAT1 complex, simultaneously suppressing MYC-driven oncogenic signaling while activating the p53-p21 tumor suppressor axis. These effects have culminated in robust antileukemic activity in preclinical models, while preserving normal peripheral blood mononuclear cell (PBMC) function. Collectively, our findings establish CXJ2080 as a next-generation CDK7-targeted therapeutic agent with enhanced efficacy and reduced hematotoxicity, showing great promise for the treatment of acute leukemia.