biostudies-literatureMathison CJNNational Institute of General Medical Sciences1912-1919https://www.ebi.ac.uk/biostudies/studies/S-EPMC8667305biostudies-literatureUnknown12(12)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 ACS medicinal chemistry lettersAntitarget Selectivity and Tolerability of Novel Pyrrolo[2,3-d]pyrimidine RET Inhibitors.PMC8667305P30 GM124169-01Jiang JMolteni VTellew JEChianelli DGao MYLee CRucker PVXie YFBursulaya BKinyamu-Akunda JMathison CJNNelson JShaffer JLi CHua SSarkisova YLi LGalkin ALi NYang YKasibhatla SHuang ZKikkawa REpple RBriones SRoland JfalseAntitarget Selectivity and Tolerability of Novel Pyrrolo[2,3-d]pyrimidine RET Inhibitors.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 2021-01-01T00:00:00Z2021 Dec2025-04-18T20:04:34.185Z2025-04-07T07:50:51.499ZS-EPMC86673053491725410.1021/acsmedchemlett.1c00450