Ian Edward David Smith
University of Cambridge
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Publication
Featured researches published by Ian Edward David Smith.
Nature Chemical Biology | 2015
Daniel P. Bondeson; Alina Mares; Ian Edward David Smith; Eunhwa Ko; Sebastien Andre Campos; Afjal H. Miah; Katie E Mulholland; Natasha Routly; Dennis L. Buckley; Jeffrey L. Gustafson; Nico Zinn; Paola Grandi; Satoko Shimamura; Giovanna Bergamini; Maria Faelth-Savitski; Marcus Bantscheff; Carly S. Cox; Deborah A. Gordon; Ryan R. Willard; John J Flanagan; Linda N. Casillas; Bartholomew J. Votta; Willem den Besten; Kristoffer Famm; Laurens Kruidenier; Paul S. Carter; John D. Harling; Ian Churcher; Craig M. Crews
The current predominant therapeutic paradigm is based on maximizing drug-receptor occupancy to achieve clinical benefit. This strategy, however, generally requires excessive drug concentrations to ensure sufficient occupancy, often leading to adverse side effects. Here, we describe major improvements to the proteolysis targeting chimeras (PROTACs) method, a chemical knockdown strategy in which a heterobifunctional molecule recruits a specific protein target to an E3 ubiquitin ligase, resulting in the targets ubiquitination and degradation. These compounds behave catalytically in their ability to induce the ubiquitination of super-stoichiometric quantities of proteins, providing efficacy that is not limited by equilibrium occupancy. We present two PROTACs that are capable of specifically reducing protein levels by >90% at nanomolar concentrations. In addition, mouse studies indicate that they provide broad tissue distribution and knockdown of the targeted protein in tumor xenografts. Together, these data demonstrate a protein knockdown system combining many of the favorable properties of small-molecule agents with the potent protein knockdown of RNAi and CRISPR.
ACS Chemical Biology | 2015
Dennis L. Buckley; Kanak Raina; Nicole Darricarrère; John Hines; Jeffrey L. Gustafson; Ian Edward David Smith; Afjal H. Miah; John D. Harling; Craig M. Crews
Small molecule-induced protein degradation is an attractive strategy for the development of chemical probes. One method for inducing targeted protein degradation involves the use of PROTACs, heterobifunctional molecules that can recruit specific E3 ligases to a desired protein of interest. PROTACs have been successfully used to degrade numerous proteins in cells, but the peptidic E3 ligase ligands used in previous PROTACs have hindered their development into more mature chemical probes or therapeutics. We report the design of a novel class of PROTACs that incorporate small molecule VHL ligands to successfully degrade HaloTag7 fusion proteins. These HaloPROTACs will inspire the development of future PROTACs with more drug-like properties. Additionally, these HaloPROTACs are useful chemical genetic tools, due to their ability to chemically knock down widely used HaloTag7 fusion proteins in a general fashion.
ACS Medicinal Chemistry Letters | 2013
Catherine Mary Alder; Martin Ambler; Amanda J. Campbell; Aurelie Cecile Champigny; Angela M. Deakin; John D. Harling; Carol A. Harris; Tim Longstaff; Sean Lynn; Aoife C. Maxwell; Chris J. Mooney; Callum Scullion; Onkar M. P. Singh; Ian Edward David Smith; Donald O. Somers; Christopher J. Tame; Gareth Wayne; Caroline Wilson; James Michael Woolven
Inhibition of Itk potentially constitutes a novel, nonsteroidal treatment for asthma and other T-cell mediated diseases. In-house kinase cross-screening resulted in the identification of an aminopyrazole-based series of Itk inhibitors. Initial work on this series highlighted selectivity issues with several other kinases, particularly AurA and AurB. A template-hopping strategy was used to identify a series of aminobenzothiazole Itk inhibitors, which utilized an inherently more selective hinge binding motif. Crystallography and modeling were used to rationalize the observed selectivity. Initial exploration of the SAR around this series identified potent Itk inhibitors in both enzyme and cellular assays.
Archive | 2013
Craig M. Crews; Dennis L. Buckley; Alessio Ciulli; William Jorgensen; Peter C. Gareiss; Inge Van Molle; Jeffrey L. Gustafson; Hyun-Seop Tae; Julien Michel; Dentin Wade Hoyer; Anke G. Roth; John David Harling; Ian Edward David Smith; Afjal Hussain Miah; Sebastien Andre Campos; Joelle Le
Archive | 2010
Catherine Mary Alder; Ian Robert Baldwin; Nicholas Paul Barton; Amanda J. Campbell; Aurelie Cecile Champigny; John David Harling; Aoife C. Maxwell; Juliet Kay Simpson; Ian Edward David Smith; Christopher John Tame; Caroline Wilson; James Michael Woolven
Archive | 2011
Catherine Mary Alder; Ian Robert Baldwin; Nicholas Paul Barton; Amanda J. Campbell; Aurelie Cecile Champigny; John David Harling; Aoife C. Maxwell; Juliet Kay Simpson; Ian Edward David Smith; Christopher John Tame; Caroline Wilson; James Michael Woolven
Archive | 2014
Sebastien Andre Campos; John David Harling; Afjal H. Miah; Ian Edward David Smith
Archive | 2017
John David Harling; Christopher E. Neipp; Israil Pendrak; Ian Edward David Smith; Lamont Roscoe Terrell; Mark Youngman
Archive | 2017
John David Harling; Christopher E. Neipp; Israil Pendrak; Ian Edward David Smith; Lamont Roscoe Terrell; Mark Youngman
Archive | 2016
John David Harling; Ian Edward David Smith