MYLS22

MYLS22 is a first-in-class small-molecule inhibitor of Optic Atrophy 1 (OPA1), a mitochondrial dynamin-like GTPase that serves as a master regulator of mitochondrial cristae morphology and fusion. In acute myeloid leukemia (AML), OPA1 is frequently upregulated as a mitochondrial adaptation to evade apoptosis and develop resistance to BH3 mimetics like venetoclax. MYLS22 selectively inhibits OPA1, leading to apoptotic cristae remodeling and the facilitated release of cytochrome c. Beyond direct apoptotic effects, MYLS22-mediated OPA1 inhibition induces metabolic vulnerabilities, rendering AML cells dependent on exogenous glutamine and sensitizing them to ferroptosis through the activation of the ATF4-regulated integrated stress response. Preclinical studies have demonstrated that MYLS22 synergizes effectively with venetoclax in AML cell lines and patient-derived xenograft models, suggesting its potential as a therapeutic strategy to overcome venetoclax resistance.