Abstract 4483: The KAT6/7 inhibitor IDE574 disrupts tumor lineage identity and drug tolerance to deliver robust antitumor activity in biomarker selected indications.

Abstract Intra-tumoral heterogeneity often limits therapy benefit due to intrinsic and adaptive phenotypic diversification via interactions between somatic variation and epigenetic regulation. Important opportunities to overcome this challenge may lie in new therapies that target obligatory lineage-specific gene regulatory programs and constrain emergence of drug tolerant cell states. Lysine acetyltransferases (KATs) are a promising epigenetic target class due to their roles in the establishment and maintenance of permissive chromatin architecture that supports both tumor lineage identity and adaptive plasticity. In particular, KAT6A, KAT6B and KAT7 collaboratively promote oncogenic transcription programs via acetylation of histone H3 at K9, K14, and K23. Preclinical modeling of dual KAT6/KAT7 inhibition has demonstrated pathway modulation and antitumor activity that is superior to selective inhibition of KAT6, highlighting the essential role of KAT7 in sustaining tumorigenic transcription factor activity. Furthermore, the clinical KAT6 inhibitor monotherapy experience in ER+ mBC indicates an opportunity to augment therapeutic benefit by maximizing pathway modulation and preventing acquired resistance. Here we describe IDE574, a potent dual KAT6/KAT7 inhibitor with high selectivity over related KAT5/KAT8 enzymes. IDE574 demonstrated robust suppression of both H3K23ac and H3K14ac in multiple cancer models. This was concomitant with selective chromatin condensation at locations typically occupied by lineage survival transcription factors including FOXA1 in NSCLC and GATA3/ESR1 in ER+ mBC. RNA-seq analysis of drug response and an unbiased evaluation of affected biological systems with a custom RAG AI method, indicated perturbation of lineage identity and epigenetic remodeling. scRNA-seq and protein profiling of PDX-derived ER+ mBC cells revealed that dual KAT6/7 blockade likely overcomes acquired resistance by inhibiting emergence of drug-tolerant persister cells and renewal of cancer stem-like cells. In contrast to selective inhibition of KAT6, IDE574 reduced ALDH+, CD133+, and CD44+/CD24- cell populations, and inhibited clonogenic capacity. Consistent with this biology, IDE574 delivered deeper and durable antitumor activity in aggressive ER+ mBC PDX models including ESR1 mutant backgrounds reported to be resistant to the clinical KAT6 inhibitor even when combined with palbociclib and fulvestrant. Pan-cancer cell viability assessments and xenograft studies with IDE574 revealed indication opportunities in addition to mBC, including predictive biomarker-associated subsets of NSCLC and bowel cancer. These preclinical findings combined with favorable drug-like properties and non-clinical safety profile support evaluation of IDE574 in the clinic as a treatment option for patients with biomarker positive disease. Citation Format: Manav Gupta, Scott R. Tyler, Nour Ghaddar, Carl Schultz, Pranav Gupta, Steven L. Spivak, Katelyn N. Lukas, Zabrisky Roland, Anjali Bisaria, Mona Khalaj, Mason Appel, Oscar Aubi, Kelly S. Trego, Parker Y. Jameson, Jacob Burch-Konda, Angelica Gonzalez-Sanchez, Brittany Cruzan, Rushika Pandya, Jay Prakash Jain, Michael E. Dalziel, Julie Deichert, Sunjay Sethi, Ivan G. Shabalin, Jonathon S. Ryan, Daniel M. Walden, Muzaffar Alam, Daniel Severance, Amber C. Donahue, Edward Chan, Rebeca Choy, Diana M. Muñoz, Richard Zang, Xin Linghu, Peter Teriete, Christian R. Frey, Yuchen Bai, Claire L. Neilan, Josh Taygerly, Paul A. Barsanti, Michael A. White, Brian T. Jones. The KAT6/7 inhibitor IDE574 disrupts tumor lineage identity and drug tolerance to deliver robust antitumor activity in biomarker selected indications abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4483.