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

Brendan Frett; Marialuisa Moccia; Francesca Carlomagno; Massimo Santoro; Hong Yu Li

doi:10.1016/j.ejmech.2014.09.023

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

Brendan Frett, Marialuisa Moccia, Francesca Carlomagno, Massimo Santoro, Hong Yu Li

Producción científica: Article › revisión exhaustiva

22 Citas (Scopus)

Resumen

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.

Idioma original	English (US)
Páginas (desde-hasta)	714-723
Número de páginas	10
Publicación	European Journal of Medicinal Chemistry
Volumen	86
DOI	https://doi.org/10.1016/j.ejmech.2014.09.023
Estado	Published - oct 30 2014
Publicado de forma externa	Sí

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

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10.1016/j.ejmech.2014.09.023

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title = "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.",

keywords = "Kinase, Lead discovery, MCR, Medicinal chemistry, RET, Targeted therapeutics",

author = "Brendan Frett and Marialuisa Moccia and Francesca Carlomagno and Massimo Santoro and Li, \{Hong Yu\}",

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T2 - Design, synthesis and evaluation

AU - Frett, Brendan

AU - Moccia, Marialuisa

AU - Carlomagno, Francesca

AU - Santoro, Massimo

AU - Li, Hong Yu

PY - 2014/10/30

Y1 - 2014/10/30

N2 - 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.

AB - 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.

KW - Kinase

KW - Lead discovery

KW - MCR

KW - Medicinal chemistry

KW - RET

KW - Targeted therapeutics

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AN - SCOPUS:84907817021

SN - 0223-5234

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SP - 714

EP - 723

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

ER -

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

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