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Published on: May 15, 2019
Structure-based identification of new orally bioavailable BRD9-PROTACs for treating acute myelocytic leukemia
Jingyu Zhang1, Haiting Duan1, Renzhao Gui2
1Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
Abstract:
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 DC50 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 Cmax 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.
Insights
A novel oral BRD9 PROTAC, C6, effectively degrades BRD9 in acute myeloid leukemia (AML) cells. C6 shows significant therapeutic potential for AML treatment due to its efficacy and favorable pharmacokinetic properties.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- BRD9 is crucial for gene transcription and chromatin remodeling, impacting acute myeloid leukemia (AML) cell survival.
- Existing BRD9 inhibitors and PROTACs face challenges in efficacy, selectivity, and druggability for AML treatment.
Purpose of the Study:
- To develop and characterize a novel, orally active BRD9 PROTAC (C6) for AML therapy.
- To evaluate the degradation efficacy, selectivity, and therapeutic potential of C6 in AML models.
Main Methods:
- Development of an orally active BRD9 PROTAC (C6) utilizing an efficient E3 ligase.
- Assessment of BRD9 degradation efficacy and selectivity using biochemical assays (DC50 values).
- In vitro evaluation of C6 activity against AML cell lines (MV4-11) and pharmacokinetic profiling (Cmax).
Main Results:
- C6 demonstrated potent and selective BRD9 degradation with a DC50 of 1.02 ± 0.52 nM, without affecting BRD4 or BRD7.
- C6 exhibited significant in vitro efficacy against the MV4-11 AML cell line.
- C6 displayed favorable oral bioavailability, with a Cmax of 3436.95 ng/mL.
Conclusions:
- C6 is a novel BRD9 PROTAC with excellent degradation properties and oral activity.
- C6 shows promise as a potential therapeutic agent for treating acute myeloid leukemia.
- Further development of C6 could overcome limitations of current BRD9-targeting strategies in AML.
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