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Antitarget selectivity and tolerability of novel pyrrolo[2,3-d]pyrimidine RET inhibitors

Mathison, Casey, Yang, Yang, Nelson, John, Huang, Zhihong, Jiang, Jiqing, Chianelli, Donatella, Rucker, Paul, Roland, Jason, Xie, Yun, Epple, Robert, Bursulaya, Badry, Lee, Christian, Gao, Mu-Yun, Shaffer, Jennifer, Briones, Sergio, Sarkisova, Yelena, Galkin, Anna, Li, Lintong, Li, Nanxin, Li, Chun, Hua, Su, Kasibhatla, Shailaja, Kinyamu-Akunda, Jacqueline, Kikkawa, Rie, Molteni, Valentina and Tellew, John (2021) Antitarget selectivity and tolerability of novel pyrrolo[2,3-d]pyrimidine RET inhibitors. ACS Medicinal Chemistry Letters. ISSN 1948-58751948-5875


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.

Item Type: Article
Date Deposited: 20 Nov 2021 00:45
Last Modified: 20 Nov 2021 00:45


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