Discovery of XYD270 as a Potent, Selective, and Orally Efficacious BRD9 PROTAC for Cancer Therapy
Yumin Huang1,2, Guizhen Cheng1,3, Xin Tang1,4
1China-New Zealand Joint Laboratory on Biomedicine and Health, Guangdong Provincial Key Laboratory of Biocomputing, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
Abstract:
BRD9, a unique component of the ncBAF complex, has emerged as a promising therapeutic target in various cancers such as synovial sarcoma (SS) and acute myeloid leukemia (AML). Herein, we report the design, synthesis, and biological evaluation of BRD9 PROTACs based on diverse cereblon-binding ligands. Through structure-activity study, we identified 32 (XYD270) as a highly potent PROTAC demonstrating excellent degradation activity in HS-SY-II cells (DC50 = 0.082 nM, Dmax = 96%) and MV4;11 cells (DC50 = 3.9 nM, Dmax = 90%). Notably, 32 displayed robust antiproliferative activity in MV4;11 cells (IC50 = 50 nM) and HS-SY-II cells (IC50 = 1.65 μM). In an MV4;11 xenograft model, once-daily administration of 32 (10 mg/kg) achieved significant tumor growth inhibition (TGI = 54%). Taken together, our findings establish 32 as a promising BRD9 PROTAC with compelling preclinical efficacy in SS and AML.
Insights
Researchers developed a novel BRD9 PROTAC, compound 32 (XYD270), demonstrating potent degradation and antiproliferative effects against synovial sarcoma and acute myeloid leukemia cells. This compound showed significant tumor growth inhibition in preclinical models.
Area of Science:
- Oncology
- Chemical Biology
- Drug Discovery
Background:
- BRD9 is a key component of the ncBAF complex and a therapeutic target in cancers like synovial sarcoma (SS) and acute myeloid leukemia (AML).
- Targeting BRD9 offers a promising strategy for cancer treatment.
Purpose of the Study:
- To design, synthesize, and evaluate novel Bromodomain-9 (BRD9) PROTACs (proteolysis-targeting chimeras) using various cereblon-binding ligands.
- To identify potent BRD9 PROTACs with significant preclinical efficacy.
Main Methods:
- Structure-activity relationship (SAR) studies were conducted to optimize PROTAC design.
- In vitro assays assessed degradation activity (DC50, Dmax) and antiproliferative effects (IC50) in relevant cancer cell lines (HS-SY-II, MV4;11).
- In vivo efficacy was evaluated using an MV4;11 xenograft mouse model.
Main Results:
- Compound 32 (XYD270) was identified as a highly potent BRD9 PROTAC.
- Compound 32 demonstrated excellent degradation activity in HS-SY-II (DC50 = 0.082 nM, Dmax = 96%) and MV4;11 cells (DC50 = 3.9 nM, Dmax = 90%).
- Significant antiproliferative activity was observed in MV4;11 (IC50 = 50 nM) and HS-SY-II cells (IC50 = 1.65 μM).
- In vivo, compound 32 (10 mg/kg) achieved 54% tumor growth inhibition in an MV4;11 xenograft model.
Conclusions:
- Compound 32 is a promising BRD9 PROTAC with potent degradation and antiproliferative activities.
- Compound 32 exhibits compelling preclinical efficacy in models of synovial sarcoma and acute myeloid leukemia.
- Further development of compound 32 warrants investigation for cancer therapy.
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