Discovery of Piperazine-Amide Derivatives as Highly Potent and Selective RET Inhibitors
文献类型：期刊论文
| 作者 | Luo, Penghao2,3; Zhang, Panpan2; Xu, Yingxuan3; He, Zhipeng2; Guo, Chenli2; Mao, Lifei2; Ye, Cheng2; Zheng, Xiaohe2; Xu, Lei1; Zhou, Houjiang2 |
| 刊名 | ACS MEDICINAL CHEMISTRY LETTERS
 |
| 出版日期 | 2025-10-08 |
| 页码 | 8 |
| 关键词 | RET KDR Selective Inhibitor Piperazine-amide |
| ISSN号 | 1948-5875 |
| DOI | 10.1021/acsmedchemlett.5c00490 |
| 英文摘要 | Aberrant activation of the rearranged during transfection (RET) proto-oncogene is a key driver of various cancer types. Given the significant unmet clinical needs, the development of highly potent and selective RET inhibitors is urgent. Herein, we report a series of compounds featuring a novel piperazine-amide scaffold, designed and synthesized from BLU-667 via sequential bioisosteric replacement, linkage truncation, and subsequent structure-activity relationship (SAR) optimization. These efforts led to the identification of compound 13, which demonstrated exceptional inhibitory potency against wild-type RET kinase (IC50 = 1.4 nM) and high selectivity (57-fold) over kinase insert domain receptor (KDR). Compound 13 also effectively suppressed the proliferation of cancer cell lines driven by activated RET mutations and gene fusions in vitro. Furthermore, it exhibited favorable oral pharmacokinetic properties in mice, demonstrating superior in vivo efficacy compared to the multikinase inhibitor cabozantinib. In conclusion, compound 13 is a promising preclinical candidate. |
| WOS关键词 | KINASE INHIBITORS ; LUNG-CANCER ; CABOZANTINIB ; GENE |
| 资助项目 | Zhejiang Hisun Pharmaceutical Co., Ltd. |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001589654300001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/321651]  |
| 专题 | 国家级研究中心_原创新药研究全国重点实验室 |
| 通讯作者 | Zhou, Houjiang; Dong, Xiaowu |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Zhejiang Hisun Pharmaceut Co Ltd, Taizhou 318099, Peoples R China 3.Zhejiang Univ, Inst Pharmaceut, Coll Pharmaceut Sci, Hangzhou 310058, Peoples R China |
| 推荐引用方式 GB/T 7714 | Luo, Penghao,Zhang, Panpan,Xu, Yingxuan,et al. Discovery of Piperazine-Amide Derivatives as Highly Potent and Selective RET Inhibitors[J]. ACS MEDICINAL CHEMISTRY LETTERS,2025:8. |
| APA | Luo, Penghao.,Zhang, Panpan.,Xu, Yingxuan.,He, Zhipeng.,Guo, Chenli.,...&Dong, Xiaowu.(2025).Discovery of Piperazine-Amide Derivatives as Highly Potent and Selective RET Inhibitors.ACS MEDICINAL CHEMISTRY LETTERS,8. |
| MLA | Luo, Penghao,et al."Discovery of Piperazine-Amide Derivatives as Highly Potent and Selective RET Inhibitors".ACS MEDICINAL CHEMISTRY LETTERS (2025):8. |
入库方式： OAI收割
来源：上海药物研究所
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