Abstract 464: Discovery and development of IST-477, a selective KAT6A histone acetyl transferase inhibitor and characterization of its anti-tumor efficacy in ER+ HER2- breast cancer and other tumor indications
Authors: Roopa Rai, M.v. Sreedhara, Samir K. Pawar, Rahul R. Nagawade, Krishna A. Putta, Mahaboobi Jaleel, Jianhong Wang, Alison L. Hannah, Leslie J. Holsinger
Journal: Cancer Research (2025)

Abstract KAT6A and its paralog KAT6B are histone acetyltransferases (HATs) which direct chromatin structural rearrangement and subsequent changes in gene transcription through acetylation of histones, primarily specific lysine residues on histone H3. Dysregulation of this epigenetic target is known to drive gene expression and tumorigenic progression in cancers and is commonly amplified at the genomic level and/or overexpressed in a number of solid tumors. An inhibitor of KAT6A and KAT6B, PF-07248144, has entered phase 2 clinical studies with durable partial responses reported in estrogen-receptor positive (ER+) HER2- breast cancer patients who had progressed on a prior endocrine therapy and CDK4/6 inhibitor (Mukohara et al, 2024, Nature Medicine 30:2242). In addition to estrogen receptor expression, transcriptional regulation of other pathways involved in tumorigenesis is known to involve KAT6A, expanding the potential for KAT6A inhibitors to be used in other indications. Isosterix has developed a series of structurally diverse small molecule KAT6 inhibitors which are potent and selective for the KAT6A paralog. Potency directed to the KAT6A paralog is believed to offer the potential for reduced off-target toxicity. Lead optimization led to a clinical development candidate IST-477, which has entered IND-enabling studies. IST-477 inhibits KAT6A-mediated histone acetylation in a variety of tumor cell lines. It reduces cell proliferation and is additive when treated in combination with CDK4/6 inhibition. Excellent anti-tumor potency has been achieved in ER+ HER2- CDx and PDx breast cancer models with this KAT6A-selective inhibitor. IST-477 has high aqueous solubility, good PK properties, including %F&amp;gt;50 in mice/rats/dogs with an estimated clearance of 0.26 mL/min/kg and half-life of 10.2 hours in humans, predicted by multi-species allometric scaling. Early repeat-dose toxicology studies indicate excellent tolerability. Efficacy of IST-477 in pharmacology models outside of breast cancer support clinical investigation of this therapeutic in other indications. IST-477 demonstrates single-agent efficacy in a number of solid tumor models including an ovarian CDx and an esophageal PDx tumor model. Pharmacologic efficacy of this targeted therapeutic will be discussed with an analysis of the relationship to KAT6A and 6B expression in these models. All IND-enabling studies to support clinical progression of IST-477 are planned for completion in mid-2025. Citation Format: Roopa Rai, M.v. Sreedhara, Samir K. Pawar, Rahul R. Nagawade, Krishna A. Putta, Mahaboobi Jaleel, Jianhong Wang, Alison L. Hannah, Leslie J. Holsinger. Discovery and development of IST-477, a selective KAT6A histone acetyl transferase inhibitor and characterization of its anti-tumor efficacy in ER+ HER2- breast cancer and other tumor indications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 464.