Open AccessEfficacy and Tolerability of Pyrazolo[1,5-a]pyrimidine RET Kinase Inhibitors for the Treatment of Lung Adenocarcinoma
Author(s) -
Casey J. N. Mathison,
D. Chianelli,
Paul V. Rucker,
John T. Nelson,
Jason Roland,
Zhihong Huang,
Yang Yang,
Jiaoyang Jiang,
Yuanyang Xie,
Robert Epple,
Badry Bursulaya,
Christian Lee,
Mu-Yun Gao,
Jennifer Shaffer,
Sergio Briones,
Yelena Sarkisova,
Anna Galkin,
Lintong Li,
Nanxin Li,
Chun Li,
Su Hua,
Shailaja Kasibhatla,
Jacqueline Kinyamu-Akunda,
Rie Kikkawa,
Valentina Molteni,
John Tellew
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00015
Subject(s) - protein kinase domain , kinase , pyrimidine , in vivo , cancer research , medicine , tolerability , pharmacology , adenocarcinoma , lung cancer , chemistry , cancer , oncology , biology , adverse effect , biochemistry , gene , microbiology and biotechnology , mutant
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 KDR (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.