First-in-class potent and selective oral KAT6A degrader development candidate, PRT13722, drives complete tumor regressions as a monotherapy with an improved pre-clinical hematological safety profile
Presenter: Jack Carter, PhD Session: Proximity-Induced Drug Discovery 2 Time: 4/21/2026 2:00:00 PM → 4/21/2026 5:00:00 PM
Authors
Monisha Sivakumar , Sarah Pawley , Corey Basch , Jimin Park , Justin Kurian , Anthony Reichelderfer , Yue Zou , Kirsten Gallagher , Miles Cowart , Joy Cote , Alexander Grego , Jessica Burtell , Amy Crossan , Michael Hulse , Anjana Agarwal , Arpita Mondal , Chun Chen , Vijay Devannah , Sina Rezazadeh , Quincy Lewis , Patrick Wen , Ken Ray , Raul Leal , Daniel Porreca , Ganfeng Cao , Neha Bhagwat , Shanthi Ganesan , Stefan Ruepp , Min Wang , Joseph Rager , Koichi Ito , Sandy Geeganage , Andrew Combs , Peggy Scherle , Andrew Buesking , Jack Carter Prelude Therapeutics, Wilmington, DE
Abstract
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 ( 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 ( 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.
Disclosure
M. Sivakumar, Prelude Therapeutics Employment, Stock Option. S. Pawley, Prelude Therapeutics Employment, Stock Option. C. Basch, Prelude Therapeutics Employment, Stock Option. J. Park, Prelude Therapeutics Employment, Stock Option. J. Kurian, Prelude Therapeutics Employment, Stock Option. A. Reichelderfer, Prelude Therapeutics Employment, Stock Option. Y. Zou, Prelude Therapeutics Employment, Stock Option. K. Gallagher, Prelude Therapeutics Employment, Stock Option. M. Cowart, Prelude Therapeutics Employment, Stock Option. J. Cote, Prelude Therapeutics Employment, Stock Option. A. Grego, Prelude Therapeutics Employment, Stock Option. J. Burtell, Prelude Therapeutics Employment, Stock Option. A. Crossan, Prelude Therapeutics Employment, Stock Option. M. Hulse, Prelude Therapeutics Employment, Stock Option. A. Agarwal, Prelude Therapeutics Employment, Stock Option. A. Mondal, Prelude Therapeutics Employment, Stock Option. C. Chen, Prelude Therapeutics Employment, Stock Option. V. Devannah, Prelude Therapeutics Employment, Stock Option. S. Rezazadeh, Prelude Therapeutics Employment, Stock Option. Q. Lewis, Prelude Therapeutics Employment, Stock Option. P. Wen, Prelude Therapeutics Employment, Stock Option. K. Ray, Prelude Therapeutics Employment, Stock Option. R. Leal, Prelude Therapeutics Employment, Stock Option. D. Porreca, Prelude Therapeutics Employment, Stock Option. G. Cao, Prelude Therapeutics Employment, Stock Option. N. Bhagwat, Prelude Therapeutics Employment, Stock Option. S. Ganesan, Prelude Therapeutics Employment, Stock Option. S. Ruepp, Prelude Therapeutics Employment, Stock Option. M. Wang, Prelude Therapeutics Employment, Stock Option. J. Rager, Prelude Therapeutics Employment, Stock Option. K. Ito, Prelude Therapeutics Employment, Stock Option. S. Geeganage, Prelude Therapeutics Employment, Stock Option. A. Combs, Prelude Therapeutics Employment, Stock Option. P. Scherle, Prelude Therapeutics Employment, Stock Option. A. Buesking, Prelude Therapeutics Employment, Stock Option. J. Carter, Prelude Therapeutics Employment, Stock, Stock Option.
Cited in
Control: 7335 · Presentation Id: 8746 · Meeting 21436