Conformational landscape of the epidermal growth factor receptor kinase reveals a mutant specific allosteric pocket
Activating mutations within the epidermal growth factor receptor (EGFR) kinase domain give rise to several cancers including Non-Small Cell Lung Cancer (NSCLC). Small molecule inhibitors targeted at these mutants have proven to be clinically successful drugs. These molecules are ATP competitive and...
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sg-ntu-dr.10356-875632023-02-28T17:02:02Z Conformational landscape of the epidermal growth factor receptor kinase reveals a mutant specific allosteric pocket Kannan, Srinivasaraghavan Venkatachalam, Gireedhar Lim, Hong Hwa Surana, Uttam Verma, Chandra School of Biological Sciences Allosteric Pocket Molecular Dynamics Simulation Activating mutations within the epidermal growth factor receptor (EGFR) kinase domain give rise to several cancers including Non-Small Cell Lung Cancer (NSCLC). Small molecule inhibitors targeted at these mutants have proven to be clinically successful drugs. These molecules are ATP competitive and rapidly result in the emergence of resistance. Recently Jia et al. [Nature, 2016, 534, 129–132] reported a small molecule inhibitor (called EAI045) that binds at an allosteric pocket, does not compete with ATP and displays high potency and selectivity towards certain activating mutants (L858R, T790M, L858R/T790M) of EGFR, with IC50 values ranging from 3 nM to 49 nM. We present here a study combining extensive molecular dynamics simulations with binding assays to provide a structural basis underlying the mechanism of binding of this molecule. It appears that in mutants, conformational destabilization of the short helix (that carries Leu858 in the wildtype), is key to the exposure of the allosteric pocket which otherwise is occluded by a set of sidechains including L858. We extend this hypothesis to show that a similar mechanism would enable the molecule to inhibit EGFRL861Q which is another oncogenic mutant and validate this with binding experiments. The screening of the human structural kinome revealed at least 12 other oncogenic kinases which carry at least one activating mutant in this disorder-prone region and hence would be amenable to allosteric inhibition by molecules such as EAI045. Our study characterizes a druggable allosteric pocket which appears to be specific to certain oncogenic mutants of the EGFR and holds therapeutic potential. ASTAR (Agency for Sci., Tech. and Research, S’pore) Published version 2018-07-31T03:32:26Z 2019-12-06T16:44:33Z 2018-07-31T03:32:26Z 2019-12-06T16:44:33Z 2018 Journal Article Kannan, S., Venkatachalam, G., Lim, H. H., Surana, U., & Verma, C. (2018). Conformational landscape of the epidermal growth factor receptor kinase reveals a mutant specific allosteric pocket. Chemical Science, 9(23), 5212-5222. 2041-6520 https://hdl.handle.net/10356/87563 http://hdl.handle.net/10220/45403 10.1039/C8SC01262H en Chemical Science © 2018 The Author(s) (published by Royal Society of Chemistry). This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. 11 p. application/pdf |
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Allosteric Pocket Molecular Dynamics Simulation Kannan, Srinivasaraghavan Venkatachalam, Gireedhar Lim, Hong Hwa Surana, Uttam Verma, Chandra Conformational landscape of the epidermal growth factor receptor kinase reveals a mutant specific allosteric pocket |
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Activating mutations within the epidermal growth factor receptor (EGFR) kinase domain give rise to several cancers including Non-Small Cell Lung Cancer (NSCLC). Small molecule inhibitors targeted at these mutants have proven to be clinically successful drugs. These molecules are ATP competitive and rapidly result in the emergence of resistance. Recently Jia et al. [Nature, 2016, 534, 129–132] reported a small molecule inhibitor (called EAI045) that binds at an allosteric pocket, does not compete with ATP and displays high potency and selectivity towards certain activating mutants (L858R, T790M, L858R/T790M) of EGFR, with IC50 values ranging from 3 nM to 49 nM. We present here a study combining extensive molecular dynamics simulations with binding assays to provide a structural basis underlying the mechanism of binding of this molecule. It appears that in mutants, conformational destabilization of the short helix (that carries Leu858 in the wildtype), is key to the exposure of the allosteric pocket which otherwise is occluded by a set of sidechains including L858. We extend this hypothesis to show that a similar mechanism would enable the molecule to inhibit EGFRL861Q which is another oncogenic mutant and validate this with binding experiments. The screening of the human structural kinome revealed at least 12 other oncogenic kinases which carry at least one activating mutant in this disorder-prone region and hence would be amenable to allosteric inhibition by molecules such as EAI045. Our study characterizes a druggable allosteric pocket which appears to be specific to certain oncogenic mutants of the EGFR and holds therapeutic potential. |
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School of Biological Sciences |
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School of Biological Sciences Kannan, Srinivasaraghavan Venkatachalam, Gireedhar Lim, Hong Hwa Surana, Uttam Verma, Chandra |
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Article |
author |
Kannan, Srinivasaraghavan Venkatachalam, Gireedhar Lim, Hong Hwa Surana, Uttam Verma, Chandra |
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Kannan, Srinivasaraghavan |
title |
Conformational landscape of the epidermal growth factor receptor kinase reveals a mutant specific allosteric pocket |
title_short |
Conformational landscape of the epidermal growth factor receptor kinase reveals a mutant specific allosteric pocket |
title_full |
Conformational landscape of the epidermal growth factor receptor kinase reveals a mutant specific allosteric pocket |
title_fullStr |
Conformational landscape of the epidermal growth factor receptor kinase reveals a mutant specific allosteric pocket |
title_full_unstemmed |
Conformational landscape of the epidermal growth factor receptor kinase reveals a mutant specific allosteric pocket |
title_sort |
conformational landscape of the epidermal growth factor receptor kinase reveals a mutant specific allosteric pocket |
publishDate |
2018 |
url |
https://hdl.handle.net/10356/87563 http://hdl.handle.net/10220/45403 |
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1759858168667570176 |