首创强效、选择性口服KAT6A降解剂开发候选药物PRT13722作为单药驱动完全的肿瘤消退，并具有改善的临床前血液学安全性特征

KAT6A is a member of the MYST family of histone acetyltransferases and is recurrently amplified in multiple cancer types, driving cancer cell growth. Targeting KAT6 has recently been clinically validated in ER+/HER2- breast cancer (BC) and is being evaluated in Phase 3 trials in combination with fulvestrant (FUL). Notably, MYST proteins (e.g. KAT6A/B, KAT7) co-regulate normal hematopoiesis and current clinical inhibitors co-target these proteins in addition to KAT6A, resulting in dose-limiting neutropenia. Further, KAT6A protein degradation has been shown to drive differential biology compared to inhibition and deeper efficacy than KAT6A/B inhibitors. With the goals of addressing the clinical incidence of neutropenia and improving efficacy, we sought to identify KAT6B-sparing KAT6A heterobifunctional degraders. Utilizing structure-based drug design, we engineered the first known bivalent TPDs to potently and selectively degrade KAT6A over KAT6B. Further optimization of the ADME and physicochemical properties provided our orally bioavailable KAT6A selective degrader development candidate, PRT13722. PRT13722(±) is a picomolar KAT6A degrader with exquisite selectivity over KAT6B (<5% D MAX ) and high oral bioavailability across species. Global proteomic and neosubstrate profiling confirmed the selectivity of PRT13722(±), including against other MYST proteins. Despite a lack of KAT6B degradation, we observed PRT13722(±) demonstrated superior (95% E MAX ) anti-proliferative activity in T47D ER+ BC cells compared to a KAT6A/Bi (43% E MAX ) and good breadth of efficacy. Unlike inhibitors, PRT13722 disrupted the KAT6A complex, driving deeper suppression of global oncogenic gene expression (e.g. ESR1 , PGR , MYC ). In numerous ER+ BC xenografts, PRT13722(±) safely drove deep and complete tumor regressions as a monotherapy (e.g. T47D TGI = 101%), unlike a clinical KAT6A/Bi plus FUL (T47D TGI = 71%), at low oral daily doses (<5 mg/kg). Repeat dose in vivo PD studies demonstrated robust KAT6A (>84%) and no KAT6B degradation at efficacious doses. Mice treated with PRT13722(±) had higher neutrophil counts than those treated with clinical exposures of a KAT6A/Bi. These findings potentially address a clinical limitation of KAT6A/Bi by reducing an overlapping toxicity with other therapeutic agents such as CDK4/6i. Indeed, PRT13722 demonstrated combinability in vitro and in vivo with CDK4/6i, PI3Ki, and endocrine therapies (ET), while maintaining activity in CDK4/6i- and ET-resistant, and ESR1 / PIK3CA mutant models. In summary, our first-in-class potent and selective oral KAT6A degrader, PRT13722, demonstrates improved efficacy and the potential for reduced off-target neutropenia compared to certain clinically validated KAT6A/B dual inhibitors. IND filing for PRT13722 is on track for mid-2026.