HEN-463

HEN-463 is a **small molecule sesquiterpene lactone derivative** that acts as a covalent inhibitor of LAS1L, developed for the selective treatment of **NPM1-mutant acute myeloid leukemia (AML)**[1][4]. Its mechanism involves **covalently binding to the C264 site of the ribosomal biogenesis protein LAS1**, inhibiting its interaction with NOL9 and obstructing the maturation of 28 S ribosomal RNA[1][4]. This interference profoundly affects the NPM1-MDM2-p53 signaling pathway, leading to the stabilization of p53 and resulting in inhibition of leukemic cell proliferation, induction of apoptosis and differentiation, and cell cycle arrest[1][4]. HEN-463 has shown efficacy especially in AML patients over 60 years old with NPM1 mutations, a population with poor prognosis and elevated LAS1 expression. In preclinical studies, combining HEN-463 with an XPO1 inhibitor (Selinexor) preserves nuclear p53 and overcomes drug resistance, further enhancing therapeutic effect[1][4]. The drug is in preclinical development, originally from Nanjing University of Chinese Medicine[4].