SOMCL-19-133

SOMCL-19-133 is a novel, highly potent, selective, and orally bioavailable small-molecule inhibitor of NEDD8-activating enzyme (NAE), a key E1 enzyme in the neddylation cascade. Developed by the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, in collaboration with the Shanghai Research Center for Modernization of Traditional Chinese Medicine, SOMCL-19-133 acts as an adenosine monophosphate (AMP) analog. It binds to NAE (specifically targeting the UBA3 subunit) and forms a covalent inhibitor-NEDD8 adduct, thereby blocking the neddylation of Cullin-RING ligases (CRLs). This inhibition leads to the accumulation of CRL substrates (such as Cdt1, p21, p27, and Wee1), triggering DNA damage, cell cycle arrest, and apoptosis in cancer cells. In preclinical studies, SOMCL-19-133 has demonstrated superior antiproliferative activity and more favorable pharmacokinetic properties compared to the first-in-class NAE inhibitor pevonedistat (MLN4924), making it a promising candidate for the treatment of solid tumors.