Discovery and preclinical characterization of novel small molecule TRK and ROS1 tyrosine kinase inhibitors for the treatment of cancer and inflammation.

Receptor tyrosine kinases (RTKs), in response to their growth factor ligands, phosphorylate and activate downstream signals important for physiological development and pathological transformation. Increased expression, activating mutations and rearrangement fusions of RTKs lead to cancer, inflammati...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Ramesh Narayanan, Muralimohan Yepuru, Christopher C Coss, Zhongzhi Wu, Matthew N Bauler, Christina M Barrett, Michael L Mohler, Yun Wang, Juhyun Kim, Linda M Snyder, Yali He, Nelson Levy, Duane D Miller, James T Dalton
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/99a4bb75c3cc4be7b28f17e6807eb989
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:99a4bb75c3cc4be7b28f17e6807eb989
record_format	dspace
spelling	oai:doaj.org-article:99a4bb75c3cc4be7b28f17e6807eb9892021-11-18T08:40:22ZDiscovery and preclinical characterization of novel small molecule TRK and ROS1 tyrosine kinase inhibitors for the treatment of cancer and inflammation.1932-620310.1371/journal.pone.0083380https://doaj.org/article/99a4bb75c3cc4be7b28f17e6807eb9892013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24386191/?tool=EBIhttps://doaj.org/toc/1932-6203Receptor tyrosine kinases (RTKs), in response to their growth factor ligands, phosphorylate and activate downstream signals important for physiological development and pathological transformation. Increased expression, activating mutations and rearrangement fusions of RTKs lead to cancer, inflammation, pain, neurodegenerative diseases, and other disorders. Activation or over-expression of ALK, ROS1, TRK (A, B, and C), and RET are associated with oncogenic phenotypes of their respective tissues, making them attractive therapeutic targets. Cancer cDNA array studies demonstrated over-expression of TRK-A and ROS1 in a variety of cancers, compared to their respective normal tissue controls. We synthesized a library of small molecules that inhibit the above indicated RTKs with picomolar to nanomolar potency. The lead molecule GTx-186 inhibited RTK-dependent cancer cell and tumor growth. In vitro and in vivo growth of TRK-A-dependent IMR-32 neuroblastoma cells and ROS1-overexpressing NIH3T3 cells were inhibited by GTx-186. GTx-186 also inhibited inflammatory signals mediated by NFκB, AP-1, and TRK-A and potently reduced atopic dermatitis and air-pouch inflammation in mice and rats. Moreover, GTx-186 effectively inhibited ALK phosphorylation and ALK-dependent cancer cell growth. Collectively, the RTK inhibitor GTx-186 has a unique kinase profile with potential to treat cancer, inflammation, and neuropathic pain.Ramesh NarayananMuralimohan YepuruChristopher C CossZhongzhi WuMatthew N BaulerChristina M BarrettMichael L MohlerYun WangJuhyun KimLinda M SnyderYali HeNelson LevyDuane D MillerJames T DaltonPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 12, p e83380 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ramesh Narayanan Muralimohan Yepuru Christopher C Coss Zhongzhi Wu Matthew N Bauler Christina M Barrett Michael L Mohler Yun Wang Juhyun Kim Linda M Snyder Yali He Nelson Levy Duane D Miller James T Dalton Discovery and preclinical characterization of novel small molecule TRK and ROS1 tyrosine kinase inhibitors for the treatment of cancer and inflammation.
description	Receptor tyrosine kinases (RTKs), in response to their growth factor ligands, phosphorylate and activate downstream signals important for physiological development and pathological transformation. Increased expression, activating mutations and rearrangement fusions of RTKs lead to cancer, inflammation, pain, neurodegenerative diseases, and other disorders. Activation or over-expression of ALK, ROS1, TRK (A, B, and C), and RET are associated with oncogenic phenotypes of their respective tissues, making them attractive therapeutic targets. Cancer cDNA array studies demonstrated over-expression of TRK-A and ROS1 in a variety of cancers, compared to their respective normal tissue controls. We synthesized a library of small molecules that inhibit the above indicated RTKs with picomolar to nanomolar potency. The lead molecule GTx-186 inhibited RTK-dependent cancer cell and tumor growth. In vitro and in vivo growth of TRK-A-dependent IMR-32 neuroblastoma cells and ROS1-overexpressing NIH3T3 cells were inhibited by GTx-186. GTx-186 also inhibited inflammatory signals mediated by NFκB, AP-1, and TRK-A and potently reduced atopic dermatitis and air-pouch inflammation in mice and rats. Moreover, GTx-186 effectively inhibited ALK phosphorylation and ALK-dependent cancer cell growth. Collectively, the RTK inhibitor GTx-186 has a unique kinase profile with potential to treat cancer, inflammation, and neuropathic pain.
format	article
author	Ramesh Narayanan Muralimohan Yepuru Christopher C Coss Zhongzhi Wu Matthew N Bauler Christina M Barrett Michael L Mohler Yun Wang Juhyun Kim Linda M Snyder Yali He Nelson Levy Duane D Miller James T Dalton
author_facet	Ramesh Narayanan Muralimohan Yepuru Christopher C Coss Zhongzhi Wu Matthew N Bauler Christina M Barrett Michael L Mohler Yun Wang Juhyun Kim Linda M Snyder Yali He Nelson Levy Duane D Miller James T Dalton
author_sort	Ramesh Narayanan
title	Discovery and preclinical characterization of novel small molecule TRK and ROS1 tyrosine kinase inhibitors for the treatment of cancer and inflammation.
title_short	Discovery and preclinical characterization of novel small molecule TRK and ROS1 tyrosine kinase inhibitors for the treatment of cancer and inflammation.
title_full	Discovery and preclinical characterization of novel small molecule TRK and ROS1 tyrosine kinase inhibitors for the treatment of cancer and inflammation.
title_fullStr	Discovery and preclinical characterization of novel small molecule TRK and ROS1 tyrosine kinase inhibitors for the treatment of cancer and inflammation.
title_full_unstemmed	Discovery and preclinical characterization of novel small molecule TRK and ROS1 tyrosine kinase inhibitors for the treatment of cancer and inflammation.
title_sort	discovery and preclinical characterization of novel small molecule trk and ros1 tyrosine kinase inhibitors for the treatment of cancer and inflammation.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/99a4bb75c3cc4be7b28f17e6807eb989
work_keys_str_mv	AT rameshnarayanan discoveryandpreclinicalcharacterizationofnovelsmallmoleculetrkandros1tyrosinekinaseinhibitorsforthetreatmentofcancerandinflammation AT muralimohanyepuru discoveryandpreclinicalcharacterizationofnovelsmallmoleculetrkandros1tyrosinekinaseinhibitorsforthetreatmentofcancerandinflammation AT christopherccoss discoveryandpreclinicalcharacterizationofnovelsmallmoleculetrkandros1tyrosinekinaseinhibitorsforthetreatmentofcancerandinflammation AT zhongzhiwu discoveryandpreclinicalcharacterizationofnovelsmallmoleculetrkandros1tyrosinekinaseinhibitorsforthetreatmentofcancerandinflammation AT matthewnbauler discoveryandpreclinicalcharacterizationofnovelsmallmoleculetrkandros1tyrosinekinaseinhibitorsforthetreatmentofcancerandinflammation AT christinambarrett discoveryandpreclinicalcharacterizationofnovelsmallmoleculetrkandros1tyrosinekinaseinhibitorsforthetreatmentofcancerandinflammation AT michaellmohler discoveryandpreclinicalcharacterizationofnovelsmallmoleculetrkandros1tyrosinekinaseinhibitorsforthetreatmentofcancerandinflammation AT yunwang discoveryandpreclinicalcharacterizationofnovelsmallmoleculetrkandros1tyrosinekinaseinhibitorsforthetreatmentofcancerandinflammation AT juhyunkim discoveryandpreclinicalcharacterizationofnovelsmallmoleculetrkandros1tyrosinekinaseinhibitorsforthetreatmentofcancerandinflammation AT lindamsnyder discoveryandpreclinicalcharacterizationofnovelsmallmoleculetrkandros1tyrosinekinaseinhibitorsforthetreatmentofcancerandinflammation AT yalihe discoveryandpreclinicalcharacterizationofnovelsmallmoleculetrkandros1tyrosinekinaseinhibitorsforthetreatmentofcancerandinflammation AT nelsonlevy discoveryandpreclinicalcharacterizationofnovelsmallmoleculetrkandros1tyrosinekinaseinhibitorsforthetreatmentofcancerandinflammation AT duanedmiller discoveryandpreclinicalcharacterizationofnovelsmallmoleculetrkandros1tyrosinekinaseinhibitorsforthetreatmentofcancerandinflammation AT jamestdalton discoveryandpreclinicalcharacterizationofnovelsmallmoleculetrkandros1tyrosinekinaseinhibitorsforthetreatmentofcancerandinflammation
_version_	1718421460393918464

Discovery and preclinical characterization of novel small molecule TRK and ROS1 tyrosine kinase inhibitors for the treatment of cancer and inflammation.

Ejemplares similares