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Lead Discovery of Type II BRAF V600E Inhibitors Targeting the Structurally Validated DFG-Out Conformation Based upon Selected Fragments

The success of the first approved kinase inhibitor imatinib has spurred great interest in the development of type II inhibitors targeting the inactive DFG-out conformation, wherein the Phe of the DFG motif at the start of the activation loop points into the ATP binding site. Nevertheless, kinase inh...

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Autores principales: Zhang, Qingwen, Zhang, Xuejin, You, Qidong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6272942/
https://www.ncbi.nlm.nih.gov/pubmed/27438814
http://dx.doi.org/10.3390/molecules21070879
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author Zhang, Qingwen
Zhang, Xuejin
You, Qidong
author_facet Zhang, Qingwen
Zhang, Xuejin
You, Qidong
author_sort Zhang, Qingwen
collection PubMed
description The success of the first approved kinase inhibitor imatinib has spurred great interest in the development of type II inhibitors targeting the inactive DFG-out conformation, wherein the Phe of the DFG motif at the start of the activation loop points into the ATP binding site. Nevertheless, kinase inhibitors launched so far are heavily biased toward type I inhibitors targeting the active DFG-in conformation, wherein the Phe of the DFG motif flips by approximately 180° relative to the inactive conformation, resulting in Phe and Asp swapping their positions. Data recently obtained with structurally validated type II inhibitors supported the conclusion that type II inhibitors are more selective than type I inhibitors. In our type II BRAF V600E inhibitor lead discovery effort, we identified phenylaminopyrimidine (PAP) and unsymmetrically disubstituted urea as two fragments that are frequently presented in FDA-approved protein kinase inhibitors. We therefore defined PAP and unsymmetrically disubstituted urea as privileged fragments for kinase drug discovery. A pharmacophore for type II inhibitors, 4-phenylaminopyrimidine urea (4-PAPU), was assembled based upon these privileged fragments. Lead compound SI-046 with BRAF V600E inhibitory activity comparable to the template compound sorafenib was in turn obtained through preliminary structure–activity relationship (SAR) study. Molecular docking suggested that SI-046 is a bona fide type II kinase inhibitor binding to the structurally validated “classical DFG-out” conformation of BRAF V600E. Our privileged fragments-based approach was shown to efficiently deliver a bona fide type II kinase inhibitor lead. In essence, the theme of this article is to showcase the strategy and rationale of our approach.
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spelling pubmed-62729422018-12-28 Lead Discovery of Type II BRAF V600E Inhibitors Targeting the Structurally Validated DFG-Out Conformation Based upon Selected Fragments Zhang, Qingwen Zhang, Xuejin You, Qidong Molecules Article The success of the first approved kinase inhibitor imatinib has spurred great interest in the development of type II inhibitors targeting the inactive DFG-out conformation, wherein the Phe of the DFG motif at the start of the activation loop points into the ATP binding site. Nevertheless, kinase inhibitors launched so far are heavily biased toward type I inhibitors targeting the active DFG-in conformation, wherein the Phe of the DFG motif flips by approximately 180° relative to the inactive conformation, resulting in Phe and Asp swapping their positions. Data recently obtained with structurally validated type II inhibitors supported the conclusion that type II inhibitors are more selective than type I inhibitors. In our type II BRAF V600E inhibitor lead discovery effort, we identified phenylaminopyrimidine (PAP) and unsymmetrically disubstituted urea as two fragments that are frequently presented in FDA-approved protein kinase inhibitors. We therefore defined PAP and unsymmetrically disubstituted urea as privileged fragments for kinase drug discovery. A pharmacophore for type II inhibitors, 4-phenylaminopyrimidine urea (4-PAPU), was assembled based upon these privileged fragments. Lead compound SI-046 with BRAF V600E inhibitory activity comparable to the template compound sorafenib was in turn obtained through preliminary structure–activity relationship (SAR) study. Molecular docking suggested that SI-046 is a bona fide type II kinase inhibitor binding to the structurally validated “classical DFG-out” conformation of BRAF V600E. Our privileged fragments-based approach was shown to efficiently deliver a bona fide type II kinase inhibitor lead. In essence, the theme of this article is to showcase the strategy and rationale of our approach. MDPI 2016-07-16 /pmc/articles/PMC6272942/ /pubmed/27438814 http://dx.doi.org/10.3390/molecules21070879 Text en © 2016 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zhang, Qingwen
Zhang, Xuejin
You, Qidong
Lead Discovery of Type II BRAF V600E Inhibitors Targeting the Structurally Validated DFG-Out Conformation Based upon Selected Fragments
title Lead Discovery of Type II BRAF V600E Inhibitors Targeting the Structurally Validated DFG-Out Conformation Based upon Selected Fragments
title_full Lead Discovery of Type II BRAF V600E Inhibitors Targeting the Structurally Validated DFG-Out Conformation Based upon Selected Fragments
title_fullStr Lead Discovery of Type II BRAF V600E Inhibitors Targeting the Structurally Validated DFG-Out Conformation Based upon Selected Fragments
title_full_unstemmed Lead Discovery of Type II BRAF V600E Inhibitors Targeting the Structurally Validated DFG-Out Conformation Based upon Selected Fragments
title_short Lead Discovery of Type II BRAF V600E Inhibitors Targeting the Structurally Validated DFG-Out Conformation Based upon Selected Fragments
title_sort lead discovery of type ii braf v600e inhibitors targeting the structurally validated dfg-out conformation based upon selected fragments
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6272942/
https://www.ncbi.nlm.nih.gov/pubmed/27438814
http://dx.doi.org/10.3390/molecules21070879
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