Synthesis and evaluation of imidazo[1,2-a]pyridine analogues of the phosphatidylinositol 3-kinase inhibitor ZSTK474

Show simple item record Rewcastle, Gordon en Gamage, Swarnalatha en Spicer, Julie en Flanagan, Jack en Denny, William en Shepherd, PR en
dc.coverage.spatial Dublin, Ireland 13-16th November 2018. en 2019-05-28T04:34:07Z en 2018-11-15 en
dc.identifier.citation 30th EORTC-NCI-AACR symposium, “Molecular Targets and Cancer Therapeutics.” 15 Nov 2018 en
dc.identifier.uri en
dc.description.abstract Background: The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in cancers, although several small molecule inhibitors of the pathway have now been identified. Our earlier work showed that replacement of one of the morpholine groups of the PI3K inhibitor 2-(difluoromethyl)-1-(4,6-di-4-morpholinyl-1,3,5-triazin-2-yl)-1H-benzimidazole (ZSTK474) with sulfonamide-containing substituents, coupled with the addition of a methoxy group at the 4-position of the benzimidazole group, produced an active class of potent PI3Kα and dual PI3Kα/mTOR inhibitors. This work culminated in the clinical trial of our lead candidate PWT33597 in 2011. Here we describe our investigation of analogues of this class of inhibitors where the benzimidazole portion of the molecule is replaced by an imidazo[1,2-a]pyridine group. Material and methods: Compounds were prepared using a heteroaryl Heck reaction procedure that involved the palladium-catalysed coupling of 2-(difluoro¬methyl)imidazo[1,2-a]pyridines with chloro, iodo or trifluoromethanesulfonyloxy (trifloxy) substituted 1,3,5-triazines or pyrimidines. Compounds prepared included imidazo[1,2-a]pyridine analogues of the known inhibitors ZSTK474, PWT33597, SN32976, MIPS-9922 and AS2541019. The compounds were tested for their inhibitory activity against the p110α, p110β, and p110δ isoforms of PI3K using Homogeneous Time Resolved Fluorescence (HTRF) assays. Results: The imidazo[1,2-a]pyridine compounds followed their benzimidazole analogues in terms of selectivity for the PI3K isoforms, but in general showed less potency in the HTRF assays. Conclusions: Using a scaffold-hopping approach we have investigated imidazo[1,2-a]pyridine analogues of the ZSTK474 class of PI3K inhibitors. The new compounds maintain the isoform selectivity of their benzimidazole analogues, but in general show less potency. en
dc.description.uri en
dc.relation.ispartof 30th EORTC-NCI-AACR symposium, “Molecular Targets and Cancer Therapeutics.” en
dc.relation.ispartofseries European Journal of Cancer en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. en
dc.rights.uri en
dc.title Synthesis and evaluation of imidazo[1,2-a]pyridine analogues of the phosphatidylinositol 3-kinase inhibitor ZSTK474 en
dc.type Conference Poster en
dc.identifier.doi 10.1016/S0959-8049(18)31491-6 en
dc.rights.holder Copyright: The authors en en
dc.rights.accessrights en
pubs.elements-id 761286 en Medical and Health Sciences en Medical Sciences en Auckland Cancer Research en Pharmacology en Science en Biological Sciences en Science Research en Maurice Wilkins Centre (2010-2014) en
pubs.record-created-at-source-date 2019-02-12 en

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