IST-477

IST-477 is a highly selective, orally bioavailable small molecule inhibitor of histone lysine acetyltransferase 6A (KAT6A) developed by Isosterix in collaboration with Sai Life Sciences. KAT6A is an epigenetic oncogene implicated in multiple cancers, particularly estrogen receptor-positive (ER+) and HER2-negative (HER2-) breast cancer, where it regulates transcription through chromatin modulation. Unlike dual KAT6A/B inhibitors, IST-477 is highly selective for the KAT6A paralog over KAT6B and other histone acetyltransferase (HAT) family members, which is hypothesized to reduce off-target toxicities. In preclinical studies, IST-477 has demonstrated robust anti-tumor efficacy as a single agent in cell line-derived (CDx) and patient-derived (PDx) xenograft models of ER+/HER2- breast cancer, as well as ovarian and esophageal cancers. It induces cell cycle arrest, senescence, and apoptosis in tumor cells, and shows additive effects when combined with CDK4/6 inhibitors.