Discovery of AS-1763: A Potent, Selective, Noncovalent, and Orally Available Inhibitor of Bruton’s Tyrosine Kinase,Journal of Medicinal Chemistry

当前位置： X-MOL 学术 › J. Med. Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Discovery of AS-1763: A Potent, Selective, Noncovalent, and Orally Available Inhibitor of Bruton’s Tyrosine Kinase
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-09-16 , DOI: 10.1021/acs.jmedchem.1c01279
Wataru Kawahata ₁ , Tokiko Asami ₁ , Takao Kiyoi ₁ , Takayuki Irie ₁ , Shigeki Kashimoto ₁ , Hatsuo Furuichi ₁ , Masaaki Sawa ₁

Affiliation

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.

中文翻译：

AS-1763 的发现：一种有效的、选择性的、非共价的、可口服的布鲁顿酪氨酸激酶抑制剂

尽管 Bruton 的酪氨酸激酶 (BTK) 已被公认为治疗 B 细胞恶性肿瘤的有效药物靶点，但对第一代共价 BTK 抑制剂的临床耐药性的出现正成为一个严重的问题。作为我们开发非共价 BTK 抑制剂的一部分，一系列新型吡咯并嘧啶被鉴定为野生型和 C481S 突变型 BTK 的非共价抑制剂。随后的先导优化导致鉴定出一种可口服、有效且选择性的 BTK 抑制剂13f (AS-1763) 作为下一代非共价 BTK 抑制剂。凭借在体内肿瘤异种移植模型中的显着疗效，AS-1763 已进入 1 期临床试验。

更新日期：2021-10-14

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11