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

ABSTRACT: 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

SUBMITTER: Mathison CJN 

PROVIDER: S-EPMC8667305 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature