Hydration effects on the efficacy of the Epidermal growth factor receptor kinase inhibitor afatinib

Abstract Small molecules targeting the EGFR tyrosine kinase domain have been used with some success at treating patients with non-small cell lung cancer driven by activating mutations in the kinase domain. The initial class of inhibitors displaced ATP noncovalently but were rendered ineffective due...

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Autores principales:	Srinivasaraghavan Kannan, Mohan R. Pradhan, Garima Tiwari, Wei-Chong Tan, Balram Chowbay, Eng Huat Tan, Daniel Shao-Weng Tan, Chandra Verma
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/145a6170f8624c79b228e5d534e4ff3b
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spelling	oai:doaj.org-article:145a6170f8624c79b228e5d534e4ff3b2021-12-02T12:32:24ZHydration effects on the efficacy of the Epidermal growth factor receptor kinase inhibitor afatinib10.1038/s41598-017-01491-z2045-2322https://doaj.org/article/145a6170f8624c79b228e5d534e4ff3b2017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01491-zhttps://doaj.org/toc/2045-2322Abstract Small molecules targeting the EGFR tyrosine kinase domain have been used with some success at treating patients with non-small cell lung cancer driven by activating mutations in the kinase domain. The initial class of inhibitors displaced ATP noncovalently but were rendered ineffective due to the development of resistance mutations in the kinase domain. These were overcome by the development of covalent inhibitors such as afatinib which also bind in the ATP pocket. However pooled analysis of two recent clinical trials LUX-3 and LUX-6 demonstrated an unprecedented overall survival benefit of afatinib over chemotherapy for the EGFR 19del , but not the EGFR L858R . In the current study we use modelling and simulations to show that structural constraints in EGFR 19del deletion result in significantly attenuated flexibilities in the binding pocket resulting in strong hydrogen and halogen bonds with afatinib in the EGFR 19del ; these constraints are modulated by buried water and result in the differential affinities of afatinib for the different mutants. SNP analysis of residues surrounding the buried water points to the likelihood of further differential effects of afatinib and provides a compelling case for investigating the effects of the SNPs towards further stratification of patients for ensuring the most effective use of afatinib.Srinivasaraghavan KannanMohan R. PradhanGarima TiwariWei-Chong TanBalram ChowbayEng Huat TanDaniel Shao-Weng TanChandra VermaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-8 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Srinivasaraghavan Kannan Mohan R. Pradhan Garima Tiwari Wei-Chong Tan Balram Chowbay Eng Huat Tan Daniel Shao-Weng Tan Chandra Verma Hydration effects on the efficacy of the Epidermal growth factor receptor kinase inhibitor afatinib
description	Abstract Small molecules targeting the EGFR tyrosine kinase domain have been used with some success at treating patients with non-small cell lung cancer driven by activating mutations in the kinase domain. The initial class of inhibitors displaced ATP noncovalently but were rendered ineffective due to the development of resistance mutations in the kinase domain. These were overcome by the development of covalent inhibitors such as afatinib which also bind in the ATP pocket. However pooled analysis of two recent clinical trials LUX-3 and LUX-6 demonstrated an unprecedented overall survival benefit of afatinib over chemotherapy for the EGFR 19del , but not the EGFR L858R . In the current study we use modelling and simulations to show that structural constraints in EGFR 19del deletion result in significantly attenuated flexibilities in the binding pocket resulting in strong hydrogen and halogen bonds with afatinib in the EGFR 19del ; these constraints are modulated by buried water and result in the differential affinities of afatinib for the different mutants. SNP analysis of residues surrounding the buried water points to the likelihood of further differential effects of afatinib and provides a compelling case for investigating the effects of the SNPs towards further stratification of patients for ensuring the most effective use of afatinib.
format	article
author	Srinivasaraghavan Kannan Mohan R. Pradhan Garima Tiwari Wei-Chong Tan Balram Chowbay Eng Huat Tan Daniel Shao-Weng Tan Chandra Verma
author_facet	Srinivasaraghavan Kannan Mohan R. Pradhan Garima Tiwari Wei-Chong Tan Balram Chowbay Eng Huat Tan Daniel Shao-Weng Tan Chandra Verma
author_sort	Srinivasaraghavan Kannan
title	Hydration effects on the efficacy of the Epidermal growth factor receptor kinase inhibitor afatinib
title_short	Hydration effects on the efficacy of the Epidermal growth factor receptor kinase inhibitor afatinib
title_full	Hydration effects on the efficacy of the Epidermal growth factor receptor kinase inhibitor afatinib
title_fullStr	Hydration effects on the efficacy of the Epidermal growth factor receptor kinase inhibitor afatinib
title_full_unstemmed	Hydration effects on the efficacy of the Epidermal growth factor receptor kinase inhibitor afatinib
title_sort	hydration effects on the efficacy of the epidermal growth factor receptor kinase inhibitor afatinib
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/145a6170f8624c79b228e5d534e4ff3b
work_keys_str_mv	AT srinivasaraghavankannan hydrationeffectsontheefficacyoftheepidermalgrowthfactorreceptorkinaseinhibitorafatinib AT mohanrpradhan hydrationeffectsontheefficacyoftheepidermalgrowthfactorreceptorkinaseinhibitorafatinib AT garimatiwari hydrationeffectsontheefficacyoftheepidermalgrowthfactorreceptorkinaseinhibitorafatinib AT weichongtan hydrationeffectsontheefficacyoftheepidermalgrowthfactorreceptorkinaseinhibitorafatinib AT balramchowbay hydrationeffectsontheefficacyoftheepidermalgrowthfactorreceptorkinaseinhibitorafatinib AT enghuattan hydrationeffectsontheefficacyoftheepidermalgrowthfactorreceptorkinaseinhibitorafatinib AT danielshaowengtan hydrationeffectsontheefficacyoftheepidermalgrowthfactorreceptorkinaseinhibitorafatinib AT chandraverma hydrationeffectsontheefficacyoftheepidermalgrowthfactorreceptorkinaseinhibitorafatinib
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Hydration effects on the efficacy of the Epidermal growth factor receptor kinase inhibitor afatinib

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