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

ABSTRACT: 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.

SUBMITTER: Frett B

PROVIDER: S-EPMC4666024 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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

Frett Brendan B Moccia Marialuisa M Carlomagno Francesca F Santoro Massimo M Li Hong-yu HY

European journal of medicinal chemistry 20140908

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. ...[more]

PMID: 25232968

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