Phase 1 study of zavondemstat (TACH101), a first-in-class KDM4 inhibitor, in patients with advanced solid tumors

Targeting the MDM2/MDMX–P53 protein-protein interaction has been widely recognized as a promising therapeutic strategy for cancer treatment. Since the structural characterization of the MDM2–P53 complex in 1996, numerous small-molecule MDM2 inhibitors have been developed. Several of these compounds—such as SAR405838, NVP-CGM097, MK-8242, RG7112, RG7388, DS-3032b, and AMG232—are currently undergoing clinical evaluation for their potential in cancer therapy.

This review presents a comprehensive and up-to-date overview of both MDM2 inhibitors and proteolysis-targeting chimera (PROTAC) degraders. It focuses on the processes involved in their discovery and development, including the identification of initial chemical starting points, optimization strategies, structure-activity relationship (SAR) analyses, binding interactions and co-crystal structures, biochemical profiling, mechanistic insights, and data from preclinical and clinical studies.

In addition, the review discusses key challenges in designing effective MDM2/MDMX inhibitors for cancer treatment. These include the complexities of achieving dual MDM2/MDMX inhibition, the emergence of acquired resistance, and the potential toxicities associated with P53 activation. Finally, future directions in this evolving field are briefly explored.