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

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

  • Eur J Med Chem. 2023 Oct 17:262:115872. doi: 10.1016/j.ejmech.2023.115872.
Jingyu Zhang 1,  Haiting Duan 1,  Renzhao Gui 2,  Mingfei Wu 1,  Liteng Shen 1,  Yuheng Jin 1,  Ao Pang 1,  Xiaoli Yu 1,  Shenxin Zeng 3,  Bo Zhang 4,  Nengming Lin 4,  Wenhai Huang 3,  Yuwei Wang 5,  Xiaojun Yao 6,  Jia Li 7,  Xiaowu Dong 1,  Yubo Zhou 8,  Jinxin Che 9
Affiliations

Affiliations

  • 1 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
  • 2 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan Tsuihang New District, Guangdong, 528400, PR China; School of Pharmacy, Zunyi Medical University, Zunyi, 563000, PR China.
  • 3 Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, 310058, PR China.
  • 4 Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, PR China.
  • 5 College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, 712000, PR China.
  • 6 Centre for Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao, 999078, PR China.
  • 7 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan Tsuihang New District, Guangdong, 528400, PR China; School of Pharmacy, Zunyi Medical University, Zunyi, 563000, PR China; National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.
  • 8 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan Tsuihang New District, Guangdong, 528400, PR China; School of Pharmacy, Zunyi Medical University, Zunyi, 563000, PR China; National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China. Electronic address: [email protected].
  • 9 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China. Electronic address: [email protected].
PMID: 39491427 DOI: 10.1016/j.ejmech.2023.115872
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.

Keywords

Acute myeloid leukemia; Bromodomain-containing protein 9; Docking; Orally bioavailable; Proteolysis-targeting chimera.

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