KAT6/7抑制剂IDE574破坏肿瘤谱系身份和耐药性，在生物标志物选择的适应症中提供强效抗肿瘤活性

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.