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

Mathison, Casey and Chianelli, Donatella and Rucker, Paul and Nelson, John and Roland, Jason and Huang, Zhihong and Yang, Yang and Jiang, Jiqing and Yun Feng, Xie and Epple, Robert and Bursulaya, Badry and Lee, Christian and Gao, Mu-Yun and Shaffer, Jennifer and Briones, Sergio and Sarkisova, Yelena and Galkin, Anna and Li, Lintong and Li, Nanxin and Li, Chun and Hua, Su and Kasibhatla, Shailaja and Kinyamu-Akunda, Jacqueline and Kikkawa, Rie and Tellew, John and Molteni, Valentina (2020) Efficacy and Tolerability of Pyrazolo[1,5-a]pyrimidine RET Kinase Inhibitors for the Treatment of Lung Adenocarcinoma. ACS Medicinal Chemistry Letters, 11 (4). pp. 558-565. ISSN 1948-58751948-5875


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.

Item Type: Article
Keywords: RET, receptor tyrosine kinase, KIF5B, tolerability profile, KDR
Date Deposited: 28 Apr 2020 00:45
Last Modified: 28 Apr 2020 00:45


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