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

1 The Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
2 Novartis Institutes for BioMedical Research, One Health Plaza, East Hanover, New Jersey 07936, United States.

PMID: 34917254 DOI: 10.1021/acsmedchemlett.1c00450

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 VEGFR2/KDR/Flk-1 or hERG inhibition in vivo, as evaluated by Miles assay and free plasma concentrations, respectively.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-141896

RET-IN-7

98.00%, RET Inhibitor

RET

Cancer

Name
Email *

	Sorry, but the email address you supplied was invalid.