2. Academic Validation
  3. Discovery of Novel Potent and Fast BTK PROTACs for the Treatment of Osteoclasts-Related Inflammatory Diseases

Discovery of Novel Potent and Fast BTK PROTACs for the Treatment of Osteoclasts-Related Inflammatory Diseases

  • J Med Chem. 2024 Feb 22;67(4):2438-2465. doi: 10.1021/acs.jmedchem.3c01414.
Junli Huang 1,  Zeli Ma 2,  Xiaopeng Peng 3,  Zichao Yang 4,  Yuhao Wu 5,  Guanghong Zhong 4,  Tianfeng Ouyang 4,  Zhen Chen 4,  Yao Liu 6,  Qirui Wang 7,  Jianjun Chen 4,  Ting Chen 2,  Zhenhua Zeng 5
Affiliations

Affiliations

  • 1 Department of Pharmacy, The People's Hospital of Guangxi Zhuang Autonomous Region & Guangxi Academy of Medical Sciences, Nanning, Guangxi 530021, China.
  • 2 Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
  • 3 Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Jiangxi Province Key Laboratory of Biomaterials and Biofabrication for Tissue Engineering, School of Pharmacy, Gannan Medical University, Ganzhou 314000, China.
  • 4 Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 5 Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China.
  • 6 Instrumental Analysis Center, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
  • 7 School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China.
PMID: 38321747 DOI: 10.1021/acs.jmedchem.3c01414
Abstract

Bruton's tyrosine kinase (Btk) is an attractive target in inflammatory and autoimmune diseases. However, the effectiveness of Btk inhibitors is limited by side effects and drug resistance. In this study, we report the development of novel Btk proteolysis targeting chimeras (PROTACs) with different classes of BTK-targeting ligands (e.g., spebrutinib) Other than ibrutinib. Compound 23 was identified as a potent and fast BTK PROTAC degrader, exhibiting outstanding degradation potency and efficiency in Mino cells (DC50, 4 h = 1.29 ± 0.3 nM, t1/2, 20 nM = 0.59 ± 0.20 h). Furthermore, compound 23 forms a stable ternary complex, as confirmed by the HTRF assay. Notably, 23 down-regulated the BTK-PLCγ2-Ca2+-NFATc1 signaling pathway activated by RANKL, thus inhibiting osteoclastogenesis and attenuating alveolar bone resorption in a mouse periodontitis model. These findings suggest that compound 23 is a potent and promising candidate for osteoclast-related inflammatory diseases, expanding the potential of BTK PROTACs.

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