Identification of two novel RET kinase inhibitors through MCR-based drug discovery: Design, synthesis and evaluation

•MCR based drug discovery led to the identification of two tractable RET leads.•From kinetic binding and modeling studies, data suggests compounds are Type-II inhibitors.•Two lead compounds were found to inhibit RET activity in vivo.

From an MCR fragment library, two novel chemical series have been developed as inhibitors of RET, which is a kinase involved in the pathology of medullary thyroid cancer (MTC). Structure activity relationship studies (SAR) identified two sub-micromolar tractable leads, 6g and 13g. 6g was confirmed to be a Type-II RET inhibitor. 13g and 6g inhibited RET in cells transformed by RET/C634. A RET DFG-out homology model was established and utilized to predict Type-II inhibitor binding modes.

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