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

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

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.
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-141896
    98.00%, RET Inhibitor
    RET