2. Academic Validation
  3. Efficacy and Tolerability of Pyrazolo[1,5- a]pyrimidine RET Kinase Inhibitors for the Treatment of Lung Adenocarcinoma

Efficacy and Tolerability of Pyrazolo[1,5- a]pyrimidine RET Kinase Inhibitors for the Treatment of Lung Adenocarcinoma

  • ACS Med Chem Lett. 2020 Feb 12;11(4):558-565. doi: 10.1021/acsmedchemlett.0c00015.
Casey J N Mathison 1,  Donatella Chianelli 1,  Paul V Rucker 1,  John Nelson 1,  Jason Roland 1,  Zhihong Huang 1,  Yang Yang 1,  Jiqing Jiang 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: 32292564 DOI: 10.1021/acsmedchemlett.0c00015
Abstract

RET (REarranged during Transfection) kinase gain-of-function aberrancies have been identified as potential oncogenic drivers in lung adenocarcinoma, along with several other Cancer types, prompting the discovery and assessment of selective inhibitors. Internal mining and analysis of relevant kinase data informed the decision to investigate a pyrazolo[1,5-a]pyrimidine scaffold, where subsequent optimization led to the identification of compound WF-47-JS03 (1), a potent RET kinase inhibitor with >500-fold selectivity against VEGFR2/KDR/Flk-1 (Kinase insert Domain Receptor) in cellular assays. In subsequent mouse in vivo studies, compound 1 demonstrated effective brain penetration and was found to induce strong regression of RET-driven tumor xenografts at a well-tolerated dose (10 mg/kg, po, qd). Higher doses of 1, however, were poorly tolerated in mice, similar to other pyrazolo[1,5-a]pyrimidine compounds at or near the efficacious dose, and indicative of the narrow therapeutic windows seen with this scaffold.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-133551
    99.63%, RET Inhibitor
    RET