Siremadlin (HDM-201): A Comprehensive Monograph on a Second-Generation MDM2 Inhibitor

Executive Summary

Siremadlin, also known as HDM-201, is an orally bioavailable, investigational small molecule developed by Novartis Oncology as a potent and highly selective inhibitor of the Human Double Minute 2 (HDM2) E3 ubiquitin ligase. The therapeutic rationale for Siremadlin is centered on disrupting the interaction between HDM2 and the p53 tumor suppressor protein. In approximately half of all human cancers, the TP53 gene remains wild-type, but its tumor-suppressive functions are abrogated by overexpression of its primary negative regulator, HDM2. By binding to HDM2 with picomolar affinity, Siremadlin prevents the HDM2-mediated ubiquitination and subsequent proteasomal degradation of p53. This leads to the stabilization and functional reactivation of p53, triggering downstream pathways that induce cell cycle arrest, senescence, and apoptosis in malignant cells.

Preclinical studies demonstrated a compelling profile for Siremadlin, characterized by high potency, exceptional selectivity for MDM2 over its homolog MDM4 (>10,000-fold), and robust anti-tumor activity in various in vivo xenograft models of cancers with wild-type TP53. A key preclinical finding that heavily influenced clinical strategy was the observation that dosing schedule dictates the molecular outcome: continuous low-dose exposure favors p21-mediated cell cycle arrest, whereas intermittent high-dose pulses preferentially induce PUMA-mediated apoptosis.