Andrew Cansfield
University of Hertfordshire
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Featured researches published by Andrew Cansfield.
Bioorganic & Medicinal Chemistry Letters | 2012
Kathryn Bell; Mihiro Sunose; Katie Ellard; Andrew Cansfield; Jess Taylor; Warren Miller; Nigel Ramsden; Giovanna Bergamini; Gitte Neubauer
Herein we describe the SAR of a novel series of 6-aryl-2-amino-triazolopyridines as potent and selective PI3Kγ inhibitors. The 6-aryl-triazolopyridine core was identified by chemoproteomic screening of a kinase focused library. Rapid chemical expansion around a bi-functional core identified the key features required for PI3Kγ activity and selectivity. The series was optimized to afford 43 (CZC19945), a potent PI3Kγ inhibitor with high oral bioavailability and selectivity over PI3Kα and PI3Kδ. Modification to the core afforded 53 (CZC24832) which showed increased selectivity over the entire kinome in particular over PI3Kβ.
Cell Cycle | 2008
Simon F. Scrace; Peter Kierstan; Jenifer Borgognoni; Lan-Zhen Wang; Sarah Denny; Joanne Wayne; Carol Bentley; Andrew Cansfield; Philip Stephen Jackson; Andrea M. Lockie; Nicola J. Curtin; David R. Newell; Douglas S. Williamson; Jonathan D. Moore
Transient treatment with small molecule CDK inhibitors is toxic to cancer cells and leads to depletion of anti-apoptotic proteins and Chk1, coupled with DNA damage and induction of apoptosis. Here we have examined, which of these phenomena are necessary for CDK inhibitors to have an anti-proliferative effect. We find that 24 hours treatment with either a primarily CDK2-specific, or a primarily CDK7/9-specific, antagonist eliminates proliferative potential even if apoptosis is blocked and the tendency of CDK inhibition to result in DNA damage is overcome by expression of recombinant Chk1. Loss of proliferative potential is correlated with irreversible suppression of biomarkers of cell cycle progression. CDK inhibitors dramatically reduced levels of the anti-apoptotic proteins, Mcl-1 and XIAP, but siRNA-mediated suppression of Mcl-1 and XIAP did not induce cell death in the osteosarcoma cells used in this study. Finally, we found that many literature CDK inhibitors do not effectively suppress the CDK/cyclin complexes responsible for cell-cycle progression at the minimum doses required to block proliferation: some are only effective after a substantial delay and may act via inhibition of CDK7.
Bioorganic & Medicinal Chemistry Letters | 2002
Christopher J. Hobbs; Rino A. Bit; Andrew Cansfield; Bill Harris; Christopher Huw Hill; Katherine L. Hilyard; Ian R. Kilford; Eric Argirios Kitas; Antonin Kroehn; Peter Lovell; David Pole; Paul Rugman; Brad S. Sherborne; Ian Edward David Smith; David R. Vesey; D.Lee Walmsley; David Whittaker; Glyn Williams; Fiona Wilson; David W. Banner; Allan Surgenor; Neera Borkakoti
Starting from the tetrapeptide Ac-pYEEI-NHMe and using a structure-based approach, we have designed and synthesised a peptidomimetic ligand for p56(lck) SH2 domain containing a conformationally restricted replacement for the two glutamate residues. We have explored replacments for the isoleucine residue in the pY+3 pocket and thus identified 1-(R)-amino-3-(S)-indaneacetic acid as the most potent replacement. We also report the X-ray crystal structures of two of the antagonists.
ACS Medicinal Chemistry Letters | 2016
Andrew Cansfield; Tammy Ladduwahetty; Mihiro Sunose; Katie Ellard; Rosemary Lynch; Anthea L. Newton; Ann Lewis; Gavin Bennett; Nico Zinn; Douglas Thomson; Anne J. Rüger; John Thomas Feutrill; Oliver Rausch; Alan P. Watt; Giovanna Bergamini
CZ415, a potent ATP-competitive mTOR inhibitor with unprecedented selectivity over any other kinase is described. In addition to a comprehensive characterization of its activities in vitro, in vitro ADME, and in vivo pharmacokinetic data are reported. The suitability of this inhibitor for studying in vivo mTOR biology is demonstrated in a mechanistic mouse model monitoring mTOR proximal downstream phosphorylation signaling. Furthermore, the compound reported here is the first ATP-competitive mTOR inhibitor described to show efficacy in a semitherapeutic collagen induced arthritis (CIA) mouse model.
Archive | 2007
Francis X. Wilson; Nigel Ramsden; Kathryn Bell; Andrew Cansfield; Svenja Burckhardt; Jess Taylor; Mihiro Sunose; David Middlemiss
Bioorganic & Medicinal Chemistry Letters | 2005
Douglas S. Williamson; Martin J. Parratt; Justin Fairfield Bower; Jonathan D. Moore; Christine M. Richardson; Pawel Dokurno; Andrew Cansfield; Geraint L. Francis; Richard J. Hebdon; Rob Howes; Philip Stephen Jackson; Andrea M. Lockie; James B. Murray; Claire L. Nunns; Jenifer Powles; Alan Robertson; Allan Surgenor; Christopher J. Torrance
Archive | 2004
Martin J. Parratt; Justin Fairfield Bower; Douglas S. Williamson; Andrew Cansfield
Bioorganic & Medicinal Chemistry Letters | 2006
Christine M. Richardson; Douglas S. Williamson; Martin J. Parratt; Jenifer Borgognoni; Andrew Cansfield; Pawel Dokurno; Geraint L. Francis; Rob Howes; Jonathan D. Moore; James B. Murray; Alan Robertson; Allan Surgenor; Christopher J. Torrance
Archive | 2008
Nigel Ramsden; Kathryn Bell; Andrew Cansfield; Jess Taylor; Mihiro Sunose; David Middlemiss; Gitte Neubauer
Archive | 2007
Giovanna Bergamini Moore; Andrew Cansfield; Nigel Ramsden; Gitte Neubauer