Antitarget Selectivity and Tolerability of Novel Pyrrolo[2,3‑d]pyrimidine RET Inhibitors

• Published in: ACS medicinal chemistry letters Vol. 12; no. 12; pp. 1912 - 1919
• Main Authors: Mathison, Casey J. N, Yang, Yang, Nelson, John, Huang, Zhihong, Jiang, Jiqing, Chianelli, Donatella, Rucker, Paul V, Roland, Jason, Xie, Yun Feng, 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, Tellew, John E
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 09.12.2021; Amer Chemical Soc; American Chemical Society (ACS)
• Subjects: Chemistry, Medicinal; Letter; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; RET; KDR; pyrrolo; receptor tyrosine kinase; Miles assay; 3-d]pyrimidine; POTENT; GENE; pyrrolo[2, 3-d]pyrimidine; KINASE INHIBITORS
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.1c00450

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.