2. Academic Validation
  3. Structural Feature Analyzation Strategies toward Discovery of Orally Bioavailable PROTACs of Bruton's Tyrosine Kinase for the Treatment of Lymphoma

Structural Feature Analyzation Strategies toward Discovery of Orally Bioavailable PROTACs of Bruton's Tyrosine Kinase for the Treatment of Lymphoma

  • J Med Chem. 2022 Jul 14;65(13):9096-9125. doi: 10.1021/acs.jmedchem.2c00324.
Jingyu Zhang 1,  Jinxin Che 1,  Xiaomin Luo 2 3,  Mingfei Wu 1,  Weijuan Kan 3,  Yuheng Jin 1,  Hanlin Wang 3 4,  Ao Pang 1,  Cong Li 3,  Wenhai Huang 5,  Shenxin Zeng 5,  Weihao Zhuang 1,  Yizhe Wu 1,  Yongjin Xu 6,  Yubo Zhou 2 3 7,  Jia Li 2 3 7,  Xiaowu Dong 1 8 9
Affiliations

Affiliations

  • 1 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, P. R. China.
  • 2 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 3 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China.
  • 4 School of Pharmacy, Fudan University, Shanghai 200032, China.
  • 5 Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou 310058, P. R. China.
  • 6 Department of Lymphoma, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou 310005, P. R. China.
  • 7 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, Tsuihang New District, Guangdong 528400, P. R. China.
  • 8 Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou 310018, P. R. China.
  • 9 Cancer Center, Zhejiang University, Hangzhou 310058, P. R. China.
PMID: 35671249 DOI: 10.1021/acs.jmedchem.2c00324
Abstract

Bruton's tyrosine kinase proteolysis-targeting chimeras (BTK-PROTACs) have emerged as a promising approach to address the limitations of Btk inhibitors. However, conducting the rational discovery of orally bioavailable BTK-PROTACs presents significant challenges. In this study, dimensionality reduction analysis and model molecule validation were utilized to identify some key structural features for improving the oral absorption of BTK-PROTACs. The results were applied to optimize the newly discovered BTK-PROTACs B1 and B2. Compound C13 was discovered with improved oral bioavailability, high Btk degradation activity, and selectivity. It exhibited inhibitory effects against different hematologic Cancer cells and attenuated the BTK-related signaling pathway. The oral administration of C13 effectively reduced Btk protein levels and suppressed tumor growth. This study led to the discovery of a new orally bioavailable BTK-PROTAC for the treatment of lymphoma, and we hope that the strategy will find wide utility.

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