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      A novel protocol for the one-pot borylation/Suzuki reaction provides easy access to hinge-binding groups for kinase inhibitors†

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      Organic & Biomolecular Chemistry
      Royal Society of Chemistry

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          Abstract

          This new microwave-assisted method provides a quick one-pot borylation/Suzuki protocol that does not require additional ligands nor double loading of catalyst.

          Abstract

          The one-pot borylation/Suzuki reaction is a very efficient means of accessing cross-coupling products of two aryl-halide partners that generally requires the use of specific catalysts or ligands and/or relatively long reaction times. This new microwave-assisted method provides a quick one-pot borylation/Suzuki reaction protocol that we applied to the synthesis of various bi- or poly-aryl scaffolds, including a variety of aryl and heteroaryl ring systems and the core frameworks of kinase inhibitors vemurafenib and GDC-0879.

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          Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036.

          Acquired resistance to ABL1 tyrosine kinase inhibitors (TKIs) through ABL1 kinase domain mutations, particularly the gatekeeper mutant T315I, is a significant problem for patients with chronic myeloid leukemia (CML). Using structure-based drug design, we developed compounds that bind to residues (Arg386/Glu282) ABL1 uses to switch between inactive and active conformations. The lead "switch-control" inhibitor, DCC-2036, potently inhibits both unphosphorylated and phosphorylated ABL1 by inducing a type II inactive conformation, and retains efficacy against the majority of clinically relevant CML-resistance mutants, including T315I. DCC-2036 inhibits BCR-ABL1(T315I)-expressing cell lines, prolongs survival in mouse models of T315I mutant CML and B-lymphoblastic leukemia, and inhibits primary patient leukemia cells expressing T315I in vitro and in vivo, supporting its clinical development in TKI-resistant Ph(+) leukemia. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Organoboron Acids and Their Derivatives as Catalysts for Organic Synthesis

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              Potent and selective pyrazole-based inhibitors of B-Raf kinase.

              Herein we describe a novel pyrazole-based class of ATP competitive B-Raf inhibitors. These inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. A subset of these inhibitors has demonstrated the ability to inhibit downstream ERK phosphorylation in LOX tumors from mouse xenograft studies.
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                Author and article information

                Journal
                Org Biomol Chem
                Org. Biomol. Chem
                Organic & Biomolecular Chemistry
                Royal Society of Chemistry
                1477-0520
                1477-0539
                21 January 2016
                1 December 2015
                : 14
                : 3
                : 963-969
                Affiliations
                [a ] The Institute of Cancer Research , Cancer Research UK Cancer Therapeutics Unit , Division of Cancer Therapeutics , 15 Cotswold Road , Sutton , Surrey SM2 5NG , UK . Email: Caroline.Springer@ 123456icr.ac.uk
                Author notes

                ‡These authors contributed equally to this paper.

                Article
                c5ob01915j
                10.1039/c5ob01915j
                4718143
                26620576
                1a9a4291-1bab-4f4c-8572-3fa5653c710e
                This journal is © The Royal Society of Chemistry 2015

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 15 September 2015
                : 24 November 2015
                Categories
                Chemistry

                Notes

                †Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ob01915j


                Organic & Biomolecular chemistry
                Organic & Biomolecular chemistry

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