Antitarget Selectivity and Tolerability of Novel Pyrrolo[2,3- d]pyrimidine RET Inhibitors PMID: 34917254

ADC Targets in Oncology

2026-04-10

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

ACS Med Chem Lett. 2021 Nov 6;12(12):1912-1919. doi: 10.1021/acsmedchemlett.1c00450.

Casey J N Mathison ¹ , Yang Yang ¹ , John Nelson ¹ , Zhihong Huang ¹ , Jiqing Jiang ¹ , Donatella Chianelli ¹ , Paul V Rucker ¹ , Jason Roland ¹ , Yun Feng Xie ¹ , Robert Epple ¹ , Badry Bursulaya ¹ , Christian Lee ¹ , Mu-Yun Gao ¹ , Jennifer Shaffer ¹ , Sergio Briones ¹ , Yelena Sarkisova ¹ , Anna Galkin ¹ , Lintong Li ¹ , Nanxin Li ¹ , Chun Li ¹ , Su Hua ¹ , Shailaja Kasibhatla ¹ , Jacqueline Kinyamu-Akunda ² , Rie Kikkawa ² , Valentina Molteni ¹ , John E Tellew ¹

Affiliations

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 minimal risk of KDR or hERG inhibition in vivo, as evaluated by Miles assay and free plasma concentrations, respectively.