2. Academic Validation
  3. Discovery of Pteridine-7(8 H)-one Derivatives as Potent and Selective Inhibitors of Bruton's Tyrosine Kinase (BTK)

Discovery of Pteridine-7(8 H)-one Derivatives as Potent and Selective Inhibitors of Bruton's Tyrosine Kinase (BTK)

  • J Med Chem. 2022 Feb 10;65(3):2694-2709. doi: 10.1021/acs.jmedchem.1c02208.
Dou Dou 1,  Yanyan Diao 1,  Wenjie Sha 1,  Rongrong Su 1,  Linjiang Tong 2,  Wenjie Li 1,  Limin Leng 1,  Lijuan Xie 1,  Zhixiao Yu 1,  Haoming Song 1,  Zihao Shen 1,  Lili Zhu 1,  Zhenjiang Zhao 1,  Hua Xie 2,  Zhuo Chen 1,  Honglin Li 1,  Yufang Xu 1
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
  • 2 Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
PMID: 35099969 DOI: 10.1021/acs.jmedchem.1c02208
Abstract

Bruton's tyrosine kinase (Btk) is an attractive therapeutic target in the treatment of Cancer, inflammation, and autoimmune diseases. Covalent and noncovalent Btk inhibitors have been developed, among which covalent Btk inhibitors have shown great clinical efficacy. However, some of them could produce adverse effects, such as diarrhea, rash, and platelet dysfunction, which are associated with the off-target inhibition of Itk and EGFR. In this study, we disclosed a series of pteridine-7(8H)-one derivatives as potent and selective covalent Btk inhibitors, which were optimized from 3z, an EGFR inhibitor previously reported by our group. Among them, compound 24a exhibited great Btk inhibition activity (IC50 = 4.0 nM) and high selectivity in both enzymatic (Itk >250-fold, EGFR >2500-fold) and cellular levels (Itk >227-fold, EGFR 27-fold). In U-937 xenograft models, 24a significantly inhibited tumor growth (TGI = 57.85%) at a 50 mg/kg dosage. Accordingly, 24a is a new Btk Inhibitor worthy of further development.

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