Browsing ICR Divisions by author "Collins, Ian"
Now showing items 1-20 of 28
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A critical evaluation of the approaches to targeted protein degradation for drug discovery.
Chopra, R; Sadok, A; Collins, I (Elsevier BV, 2019-04-03)There is a great deal of excitement around the concept of targeting proteins for degradation as an alternative to conventional inhibitory small molecules and antibodies. Protein degradation can be undertaken by bifunctional ... -
A fragment-based approach applied to a highly flexible target: Insights and challenges towards the inhibition of HSP70 isoforms.
Jones, AM; Westwood, IM; Osborne, JD; Matthews, TP; Cheeseman, MD; et al. (NATURE PORTFOLIO, 2016-10-06)The heat shock protein 70s (HSP70s) are molecular chaperones implicated in many cancers and of significant interest as targets for novel cancer therapies. Several HSP70 inhibitors have been reported, but because the majority ... -
A Mitsunobu reaction to functionalized cyclic and bicyclic <i>N</i>-arylamines
Gill, DM; Iveson, M; Collins, I; Jones, AM (PERGAMON-ELSEVIER SCIENCE LTD, 2018-01-17)The scope of an unexpected Mitsunobu cyclisation to prepare N-arylated Fsp3-enriched azacycles was investigated. In the current study, we have identified whether a pKa-dependent Mitsunobu cyclodehydration or a pKa-independent ... -
AMPK-independent inhibition of human macrophage ER stress response by AICAR.
Boß, M; Newbatt, Y; Gupta, S; Collins, I; Brüne, B; et al. (NATURE PORTFOLIO, 2016-08-26)Obesity-associated insulin resistance is driven by inflammatory processes in response to metabolic overload. Obesity-associated inflammation can be recapitulated in cell culture by exposing macrophages to saturated fatty ... -
Binding to an Unusual Inactive Kinase Conformation by Highly Selective Inhibitors of Inositol-Requiring Enzyme 1α Kinase-Endoribonuclease.
Colombano, G; Caldwell, JJ; Matthews, TP; Bhatia, C; Joshi, A; et al. (AMER CHEMICAL SOC, 2019-02-19)A series of imidazo[1,2- b]pyridazin-8-amine kinase inhibitors were discovered to allosterically inhibit the endoribonuclease function of the dual kinase-endoribonuclease inositol-requiring enzyme 1α (IRE1α), a key component ... -
Chemical approaches to targeted protein degradation through modulation of the ubiquitin-proteasome pathway.
Collins, I; Wang, H; Caldwell, JJ; Chopra, R (PORTLAND PRESS LTD, 2017-03-15)Manipulation of the ubiquitin-proteasome system to achieve targeted degradation of proteins within cells using chemical tools and drugs has the potential to transform pharmacological and therapeutic approaches in cancer ... -
CHK1 Inhibition Is Synthetically Lethal with Loss of B-Family DNA Polymerase Function in Human Lung and Colorectal Cancer Cells.
Rogers, RF; Walton, MI; Cherry, DL; Collins, I; Clarke, PA; et al. (AMER ASSOC CANCER RESEARCH, 2020-04-15)Checkpoint kinase 1 (CHK1) is a key mediator of the DNA damage response that regulates cell-cycle progression, DNA damage repair, and DNA replication. Small-molecule CHK1 inhibitors sensitize cancer cells to genotoxic ... -
Demonstrating In-Cell Target Engagement Using a Pirin Protein Degradation Probe (CCT367766).
Chessum, NEA; Sharp, SY; Caldwell, JJ; Pasqua, AE; Wilding, B; et al. (AMER CHEMICAL SOC, 2018-02-08)Demonstrating intracellular protein target engagement is an essential step in the development and progression of new chemical probes and potential small molecule therapeutics. However, this can be particularly challenging ... -
Discovery and Characterization of a Cryptic Secondary Binding Site in the Molecular Chaperone HSP70
O'Connor, S; Le Bihan, Y; Westwood, I; Liu, M; Van Montfort, R; et al. (MDPI AG, 2022-01-26) -
Encoding BRAF inhibitor functions in protein degraders.
Miller, DSJ; Voell, SA; Sosič, I; Proj, M; Rossanese, OW; et al. (ROYAL SOC CHEMISTRY, 2022-06-22)Various BRAF kinase inhibitors were developed to treat cancers carrying the BRAFV600E mutation. First-generation BRAF inhibitors could lead to paradoxical activation of the MAPK pathway, limiting their clinical usefulness. ... -
Evolution of kinase polypharmacology across HSP90 drug discovery.
Antolin, AA; Clarke, PA; Collins, I; Workman, P; Al-Lazikani, B (CELL PRESS, 2021-10-21)Most small molecules interact with several target proteins but this polypharmacology is seldom comprehensively investigated or explicitly exploited during drug discovery. Here, we use computational and experimental methods ... -
Exploiting Protein Conformational Change to Optimize Adenosine-Derived Inhibitors of HSP70.
Cheeseman, MD; Westwood, IM; Barbeau, O; Rowlands, M; Dobson, S; et al. (AMER CHEMICAL SOC, 2016-05-26)HSP70 is a molecular chaperone and a key component of the heat-shock response. Because of its proposed importance in oncology, this protein has become a popular target for drug discovery, efforts which have as yet brought ... -
Fragment growing to retain or alter the selectivity of anchored kinase hinge-binding fragments
Allen, CE; Welford, AJ; Matthews, TP; Caldwell, JJ; Collins, I (ROYAL SOC CHEMISTRY, 2014-01-01)<p>The selectivity patterns of kinase hinge-binding fragments can be retained during fragment growing, suggesting a new way to control poly-pharmacology.</p> -
Fragment-based screening identifies molecules targeting the substrate-binding ankyrin repeat domains of tankyrase.
Pollock, K; Liu, M; Zaleska, M; Meniconi, M; Pfuhl, M; et al. (NATURE PORTFOLIO, 2019-12-13)The PARP enzyme and scaffolding protein tankyrase (TNKS, TNKS2) uses its ankyrin repeat clusters (ARCs) to bind a wide range of proteins and thereby controls diverse cellular functions. A number of these are implicated in ... -
Genome-Protective Topoisomerase 2a-Dependent G2 Arrest Requires p53 in hTERT-Positive Cancer Cells.
Lockwood, N; Martini, S; Lopez-Pardo, A; Deiss, K; Segeren, HA; et al. (American Association for Cancer Research (AACR), 2022-05-03)UNLABELLED: Topoisomerase 2a (Topo2a)-dependent G2 arrest engenders faithful segregation of sister chromatids, yet in certain tumor cell lines where this arrest is dysfunctional, a PKCε-dependent failsafe pathway can be ... -
Identifying and Validating Tankyrase Binders and Substrates: A Candidate Approach.
Pollock, K; Ranes, M; Collins, I; Guettler, S (Springer New York, 2017-01-01)The poly(ADP-ribose)polymerase (PARP) enzyme tankyrase (TNKS/ARTD5, TNKS2/ARTD6) uses its ankyrin repeat clusters (ARCs) to recognize degenerate peptide motifs in a wide range of proteins, thereby recruiting such proteins ... -
Labelled chemical probes for demonstrating direct target engagement in living systems.
Prevet, H; Collins, I (FUTURE SCI LTD, 2019-05-24)Demonstrating target engagement in living systems can help drive successful drug discovery. Target engagement and occupancy studies in cells confirm direct binding of a ligand to its intended target protein and provide the ... -
Metabolomic changes of the multi (-AGC-) kinase inhibitor AT13148 in cells, mice and patients are associated with NOS regulation.
Pal, A; Asad, Y; Ruddle, R; Henley, AT; Swales, K; et al. (SPRINGER, 2020-04-13)INTRODUCTION: To generate biomarkers of target engagement or predictive response for multi-target drugs is challenging. One such compound is the multi-AGC kinase inhibitor AT13148. Metabolic signatures of selective signal ... -
Molecular mechanisms of human IRE1 activation through dimerization and ligand binding.
Joshi, A; Newbatt, Y; McAndrew, PC; Stubbs, M; Burke, R; et al. (IMPACT JOURNALS LLC, 2015-05-30)IRE1 transduces the unfolded protein response by splicing XBP1 through its C-terminal cytoplasmic kinase-RNase region. IRE1 autophosphorylation is coupled to RNase activity through formation of a back-to-back dimer, although ... -
Multiparameter Lead Optimization to Give an Oral Checkpoint Kinase 1 (CHK1) Inhibitor Clinical Candidate: (R)-5-((4-((Morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737).
Osborne, JD; Matthews, TP; McHardy, T; Proisy, N; Cheung, K-MJ; et al. (AMER CHEMICAL SOC, 2016-06-09)Multiparameter optimization of a series of 5-((4-aminopyridin-2-yl)amino)pyrazine-2-carbonitriles resulted in the identification of a potent and selective oral CHK1 preclinical development candidate with in vivo efficacy ...