2. Academic Validation
  3. 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.
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 KDR 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抑制剂
    RET
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