AU-24118

AU-24118 is a first-in-class, orally bioavailable proteolysis targeting chimera (PROTAC) compound designed to selectively degrade the ATPase subunits of the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex, specifically targeting SMARCA2, SMARCA4, and PBRM1. AU-24118 utilizes a CRBN-based degradation strategy, binding the bromodomains of SMARCA2 and SMARCA4 via its bait moiety, while its ligand moiety recruits the cereblon (CRBN) E3 ubiquitin ligase, leading to proteasomal degradation of the target proteins. In preclinical studies, AU-24118 demonstrated potent antitumor activity in castration-resistant prostate cancer (CRPC) models, inducing tumor regression both as monotherapy and in combination with enzalutamide (an androgen receptor antagonist). AU-24118 has favorable oral bioavailability (33.4% in mice), a dose-proportional pharmacokinetic profile, and an encouraging preclinical safety profile, with minimal toxicity observed at the maximum tolerated dose. Experiments show that candidates acquired resistance through SMARCA4 bromodomain mutations and ABCB1 overexpression, which can be reversed with the ABCB1 inhibitor zosuquidar. AU-24118 is positioned for further preclinical development and potential clinical translation in enhancer-driven cancers[1][2][3][4][5][9][10][11].