一种具有同类最佳潜力和良好药代动力学特征的高选择性KAT6/7双重抑制剂

A growing body of published studies suggested the important role for epigenetic regulation in promoting tumor heterogeneity. Targeting these epigenetic proteins becomes an exciting and attainable approach for several cancer types with unmet clinical needs. MYST-family acetyltransferases, KAT6A/B and KAT7 (HBO1), maintain promoter-proximal H3 acetylation (e.g., H3K23ac, H3K14ac) that sustains lineage transcription in multiple cancers. First-generation KAT6-selective agents have shown early clinical activity in ER + /HER2 − breast cancer but can produce predominantly cytostatic responses. We here report an orally bioavailable dual KAT6/7 inhibitor, KC1086, designed to produce deeper promoter closure, broaden lineage program suppression, and translate into tumor regressions with superior efficacy and a favorable safety window. KC1086 showed sub-10 nM potency on KAT6A/B and potent KAT7 inhibition (IC₅₀ around 16 nM) with wide selectivity over KAT5/8. In addition, KC1086 retained activity under elevated Acetyl-CoA (AcCoA), indicating reduced co-factor competition liability. Unlike PF-07248144, KC1086 did not drive significant Malonyl-CoA accumulation, while maintaining on-target AcCoA modulation, suggesting potentially much less hepatotoxicity. In ER + breast cancer cells, KC1086 durably suppressed H3K23ac/H3K14ac, which outperformed PF-07248144 on biomarker depth and duration. KC1086 monotherapy exhibited strong tumor growth inhibition in various xenograft models. Combinations of KC1086 further demonstrated enhanced efficacy: (i) with Palbociclib (CDK4/6 inhibitor) (TGI 101%) in ZR-75-1 ER + breast cancer xenograft model; (ii) with Fulvestrant (Estrogen Receptor Antagonist) (TGI 83%) in xxT47D breast cancer models yielding tumor regressions and survival benefit. Furthermore, KC1086 demonstrated favorable PK profile and significant safety window: linear PK, high oral bioavailability, minimum drug accumulation and clean safety pharmacology (eg. CV, CNS and respiratory). In conclusion, we demonstrated equipotent dual inhibition of KAT6/7 delivering potentially deeper chromatin closure than KAT6-selective blockade, which translated into robust monotherapy activity and combination synergy across ER + breast cancer, ovarian cancer as well as other tumor models, with favorable preclinical safety. These data supported clinical development of KC1086 as a dual KAT6/7 inhibitor with best-in-class potential.