HMAK101

HMAK101 is a first-in-class, brain-penetrant proteolysis-targeting chimera (PROTAC) designed to degrade survivin (BIRC5), a protein highly expressed in aggressive brain tumors like glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG). Developed by researchers at Northwestern University and the University of Washington, HMAK101 functions by recruiting the cereblon (CRBN) E3 ubiquitin ligase to survivin, leading to its ubiquitination and subsequent degradation via the proteasome. This degradation overcomes survivin-mediated radiation resistance, inducing DNA damage, G2/M cell cycle arrest, and apoptosis. Preclinical studies in mouse, rat, and non-human primate models have demonstrated that HMAK101 effectively crosses the blood-brain barrier, accumulates in tumor tissue, and significantly enhances the efficacy of radiation therapy, prolonging survival in orthotopic tumor models with minimal systemic toxicity.