| Autor: |
Zhihong Huang, Jennifer Shaffer, Badry Bursulaya, Anna Galkin, Rie Kikkawa, Yelena Sarkisova, Su Hua, John Tellew, Yang Yang, Paul Vincent Rucker, Robert Epple, Jiqing Jiang, Nanxin Li, Chianelli Donatella, Jason Roland, Lintong Li, Sergio Briones, Casey J. N. Mathison, Valentina Molteni, Jacqueline Kinyamu-Akunda, Mu-Yun Gao, John Nelson, Christian C. Lee, Yun Feng Xie, Shailaja Kasibhatla, Chun Li |
| Rok vydání: |
2021 |
| Předmět: |
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| Zdroj: |
ACS Med Chem Lett |
| ISSN: |
1948-5875 |
| DOI: |
10.1021/acsmedchemlett.1c00450 |
| Popis: |
[Image: see text] The selective inhibition of RET kinase as a treatment for relevant cancer types including lung adenocarcinoma has garnered considerable interest in recent years and prompted a variety of efforts toward the discovery of small-molecule therapeutics. Hits uncovered via the analysis of archival kinase data ultimately led to the identification of a promising pyrrolo[2,3-d]pyrimidine scaffold. The optimization of this pyrrolo[2,3-d]pyrimidine core resulted in compound 1, which demonstrated potent in vitro RET kinase inhibition and robust in vivo efficacy in RET-driven tumor xenografts upon multiday dosing in mice. The administration of 1 was well-tolerated at established efficacious doses (10 and 30 mg/kg, po, qd), and plasma exposure levels indicated a minimal risk of KDR or hERG inhibition in vivo, as evaluated by Miles assay and free plasma concentrations, respectively. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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