期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 64, 期 19, 页码 14129-14141出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c01279
关键词
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The study identified a series of novel noncovalent BTK inhibitors, among which 13f (AS-1763) as a next-generation noncovalent BTK inhibitor, showed good oral availability, potency, and selectivity, with significant efficacy in in vivo tumor xenograft models, and has advanced to phase 1 clinical trials.
Although Bruton's tyrosine kinase (BTK) has been recognized as a validated drug target for the treatment of B-cell malignances, the emergence of clinical resistance to the first-generation covalent BTK inhibitors is becoming a serious concern. As a part of our effort to develop noncovalent BTK inhibitors, a series of novel pyrrolopyrimidines was identified as noncovalent inhibitors of both the wild-type and C481S mutant BTKs. Subsequent lead optimization led to the identification of an orally available, potent, and selective BTK inhibitor 13f (AS-1763) as a next-generation noncovalent BTK inhibitor. With significant efficacies in vivo tumor xenograft models, AS-1763 has advanced to phase 1 clinical trials.
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