Abstract 3217: Discovery of novel inhibitors of the epigenetic regulator Kat6a histone acetyl transferase and characterization of their anti-tumor activity
Authors: Holsinger Leslie J. , Rai Roopa , Nagawade Rahul R. , Pal Benoy K. , Pawar Samir G. , Putta Krishna Anand , S.C. Somashekar , Jaleel Mahaboobi , Wang Jianhong , Hannah Alison L. 
Published: March 2024

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. KAT6A is modified in cancer, including genomic amplification, overexpression, mutation, as well as genetic rearrangement, resulting in the production of fusion proteins. Dysregulation of this MYST family member and its acetyl transferase activity is known to drive gene expression and tumorigenic progression in cancers. An inhibitor of KAT6A and KAT6B entered phase 1 clinical trials (NCT04606446). With continuous daily dosing, durable partial responses were seen in estrogen-receptor positive (ER+) breast cancer patients who had progressed on a prior endocrine therapy and CDK4/6 inhibitor. In that study, evidence of dose dependent pharmacodynamics (H3K23Ac inhibition) was observed in peripheral blood mononuclear cells and paired tumor biopsies (Sommerhalder, ASCO2023). Isosterix has developed a series of structurally diverse small molecule KAT6A-selective inhibitors which engage at the active site in the acetyl CoA substrate binding pocket. Lead compounds are selective for KAT6A and have significant potency and cellular activity in a variety of assays; they inhibit KAT6A-mediated histone acetylation in a biochemical assay as well as pharmacodynamic dose-dependent inhibition of histone acetylation in the breast cancer tumor cell line ZR-75-1. These compounds reduce cell viability of ZR-75-1 in 10 days with continuous compound administration, confirming the dependence of this cell line on KAT6A acetyl transferase activity for proliferation and cell cycle progression. Lead inhibitors are orally bioavailable with excellent pharmacokinetic properties in rodents. They demonstrate dose-dependent anti-tumor efficacy with minimal weight loss with continuous daily dosing in mouse xenograft tumor models. Inhibitors against this novel epigenetic target demonstrate the potential for efficacy in not only ER+ breast cancer but also other tumor indications which exhibit transcriptional induction dependent on KAT6A-directed chromatin remodeling. Selection of a lead candidate is planned for early 2024 with IND enabling studies to follow.
Citation Format: Leslie J. Holsinger, Roopa Rai, Rahul R. Nagawade, Benoy K. Pal, Samir G. Pawar, Krishna Anand Putta, Somashekar S.C., Mahaboobi Jaleel, Jianhong Wang, Alison L. Hannah. Discovery of novel inhibitors of the epigenetic regulator Kat6a histone acetyl transferase and characterization of their anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3217.