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

Pharmacology and Toxicology

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

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.

Original language	English (US)
Pages (from-to)	714-723
Number of pages	10
Journal	European journal of medicinal chemistry
Volume	86
DOIs	https://doi.org/10.1016/j.ejmech.2014.09.023
State	Published - Oct 30 2014

Keywords

Kinase
Lead discovery
MCR
Medicinal chemistry
RET
Targeted therapeutics

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

Access to Document

10.1016/j.ejmech.2014.09.023

Cite this

@article{93e053de441a455bbafc6c16e5a46b40,

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}",

note = "Publisher Copyright: {\textcopyright} 2014 Published by Elsevier Masson SAS.",

year = "2014",

month = oct,

day = "30",

doi = "10.1016/j.ejmech.2014.09.023",

language = "English (US)",

volume = "86",

pages = "714--723",

journal = "European journal of medicinal chemistry",

issn = "0223-5234",

publisher = "Elsevier Masson SAS",

}

TY - JOUR

T1 - Identification of two novel RET kinase inhibitors through MCR-based drug discovery

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

UR - http://www.scopus.com/inward/record.url?scp=84907817021&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84907817021&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2014.09.023

DO - 10.1016/j.ejmech.2014.09.023

M3 - Article

C2 - 25232968

AN - SCOPUS:84907817021

SN - 0223-5234

VL - 86

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this