Structure-based identification of new orally bioavailable BRD9-PROTACs for treating acute myelocytic leukemia.

BRD9 is essential in regulating gene transcription and chromatin remodeling, and blocking BRD9 profoundly affects the survival of AML cells. However, the inhibitors of BRD9 suffer from various drawbacks, including poor phenotype and selectivity, and BRD9 PROTACs still face the challenge of druggability, which limits the development of blocking BRD9 in AML. This study described an oral activity BRD9 PROTAC C6 by recruiting the highly efficient E3 ligase. C6 demonstrated remarkable efficacy and selectivity in BRD9 degradation with a BRD9 degradation DC 50 value of 1.02 ± 0.52 nM and no degradation of BRD4 or BRD7. Moreover, our findings highlighted its therapeutic potential, as evidenced by profound in vitro activity against the AML cell line MV4-11. Furthermore, C6 exhibited superior oral activity, with a C max value of 3436.95 ng/mL. These findings demonstrated that C6 , as a novel BRD9 PROTAC with remarkable pharmacodynamic and pharmacokinetic properties, had the potential to be developed as a promising therapeutic agent for AML treatment. [Display omitted] • A new PROTAC C6 with potent and selective BRD9 degradation activity was identified. • Compound C6 showed potent MV4-11 inhibition activity based on rational design. • C6 exhibited significantly oral activity in ICR mice with the Cmax value of 3436.95 ng/mL. [ABSTRACT FROM AUTHOR]