Efficacy and tolerability of pyrazolo[1,5-a]pyrimidine RET kinase inhibitors for the treatment of lung adenocarcinoma

RET 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 optimi-zation led to the identification of compound WF-47-JS03, a potent RET kinase inhibitor with >500-fold selectivity against KDR in cellular assays. In subsequent mouse in vivo studies, compound WF-47-JS03 demonstrated effective brain penetra-tion 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 WF-47-JS03, however, were poorly tolerated in mice, similar to other pyrazolo[1,5-a]pyrimidine com-pounds at or near the efficacious dose, and indicative of the narrow therapeutic windows seen with this scaffold.