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  • Journal article
    Goya Grocin A, Kallemeijn W, Tate E, 2021,

    Targeting methionine aminopeptidase 2 in cancer, obesity and autoimmunity

    , Trends in Pharmacological Sciences, Vol: 42, Pages: 870-882, ISSN: 0165-6147

    For over three decades, methionine aminopeptidase 2 (MetAP2) has been a tentative drug target for the treatment of cancer, obesity, and autoimmune diseases. Currently, no MetAP2 inhibitors (MetAP2i) have reached the clinic yet, despite considerable investment by major pharmaceutical companies. Here, we summarize the key series of MetAP2i developed to date and discuss their clinical development, progress, and issues. We coalesce the currently disparate knowledge regarding MetAP2i mechanism of action and discuss discrepancies across varied studies. Finally, we highlight the current knowledge gaps that need to be addressed to enable successful development of MetAP2 inhibitors in clinical settings.

  • Journal article
    Panyain N, Godinat A, Thawani AR, Lachiondo-Ortega S, Mason K, Elkhalifa S, Smith LM, Harrigan JA, Tate EWet al., 2021,

    Activity-based protein profiling reveals deubiquitinase and aldehyde dehydrogenase targets of a cyanopyrrolidine probe

    , RSC Medicinal Chemistry, Vol: 12, Pages: 1935-1943, ISSN: 2632-8682

    Ubiquitin carboxy-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme (DUB), is a potential drug target in various cancers, and liver and lung fibrosis. However, bona fide functions and substrates of UCHL1 remain poorly understood. Herein, we report the characterization of UCHL1 covalent inhibitor MT16-001 based on a thiazole cyanopyrrolidine scaffold. In combination with chemical proteomics, a closely related activity-based probe (MT16-205) was used to generate a comprehensive quantitative profile for on- and off-targets at endogenous cellular abundance. Both compounds are selective for UCHL1 over other DUBs in intact cells but also engage a range of other targets with good selectivity over the wider proteome, including aldehyde dehydrogenases, redox-sensitive Parkinson’s disease related protein PARK7, and glutamine amidotransferase. Taken together, these results underline the importance of robust profiling of activity-based probes as chemical tools and highlight the cyanopyrrolidine warhead as a versatile platform for liganding diverse classes of protein with reactive cysteine residues which can be used for further inhibitor screening, and as a starting point for inhibitor development.

  • Journal article
    Kennedy C, Goya Grocin A, Kovacic T, Singh R, Tate E, Ward J, Shenoy Aet al., 2021,

    A probe for NLRP3 inflammasome inhibitor MCC950 identifies carbonic anhydrase 2 as a novel target

    , ACS Chemical Biology, Vol: 16, Pages: 982-990, ISSN: 1554-8929

    Inhibition of inflammasome and pyroptotic pathways are promising strategies for clinical treatment of autoimmune and inflammatory disorders. MCC950, a potent inhibitor of the NLR-family inflammasome pyrin domain-containing 3 (NLRP3) protein, has shown encouraging results in animal models for a range of conditions; however, until now, no off-targets have been identified. Herein, we report the design, synthesis, and application of a novel photoaffinity alkyne-tagged probe for MCC950 (IMP2070) which shows direct engagement with NLRP3 and inhibition of inflammasome activation in macrophages. Affinity-based chemical proteomics in live macrophages identified several potential off-targets, including carbonic anhydrase 2 (CA2) as a specific target of IMP2070, and independent cellular thermal proteomic profiling revealed stabilization of CA2 by MCC950. MCC950 displayed noncompetitive inhibition of CA2 activity, confirming carbonic anhydrase as an off-target class for this compound. These data highlight potential biological mechanisms through which MCC950 and derivatives may exhibit off-target effects in preclinical or clinical studies.

  • Journal article
    Lovell S, Zhang L, Kryza T, Neodo A, Bock N, De Vita E, Williams E, Engelsberger E, Xu C, Bakker A, Maneiro M, Tanaka R, Bevan C, Clements J, Tate Eet al., 2021,

    A suite of activity-based probes to dissect the KLK activome in drug-resistant prostate cancer

    , Journal of the American Chemical Society, Vol: 143, Pages: 8911-8924, ISSN: 0002-7863

    Kallikrein-related peptidases (KLKs) are a family of secreted serine proteases, which form a network (the KLK activome) with an important role in proteolysis and signaling. In prostate cancer (PCa), increased KLK activity promotes tumor growth and metastasis through multiple biochemical pathways, and specific quantification and tracking of changes in the KLK activome could contribute to validation of KLKs as potential drug targets. Herein we report a technology platform based on novel activity-based probes (ABPs) and inhibitors enabling simultaneous orthogonal analysis of KLK2, KLK3, and KLK14 activity in hormone-responsive PCa cell lines and tumor homogenates. Importantly, we identifed a significant decoupling of KLK activity and abundance and suggest that KLK proteolysis should be considered as an additional parameter, along with the PSA blood test, for accurate PCa diagnosis and monitoring. Using selective inhibitors and multiplexed fluorescent activity-based protein profiling (ABPP), we dissect the KLK activome in PCa cells and show that increased KLK14 activity leads to a migratory phenotype. Furthermore, using biotinylated ABPs, we show that active KLK molecules are secreted into the bone microenvironment by PCa cells following stimulation by osteoblasts suggesting KLK-mediated signaling mechanisms could contribute to PCa metastasis to bone. Together our findings show that ABPP is a powerful approach to dissect dysregulation of the KLK activome as a promising and previously underappreciated therapeutic target in advanced PCa.

  • Journal article
    Lanyon-Hogg T, Ritzefeld M, Zhang L, Pogranyi B, Mondal M, Sefer L, Johnston CD, Coupland CE, Andrei SA, Newington J, Magee AI, Siebold C, Tate EWet al., 2021,

    Photochemical probe identification of the small-molecule binding site in a mammalian membrane-bound O-acyltransferase

    , Angewandte Chemie International Edition, Vol: 60, Pages: 13542-13547, ISSN: 1433-7851

    The mammalian membrane‐bound O ‐acyltransferase (MBOAT) superfamily is involved in biological processes including growth, development and appetite sensing. MBOATs are attractive drug targets in cancer and obesity; however, information on the binding site and molecular mechanisms underlying small‐molecule inhibition is elusive. This study reports rational development of a photochemical probe to interrogate a novel small‐molecule inhibitor binding site in the human MBOAT Hedgehog acyltransferase (HHAT). Structure‐activity relationship investigation identified single enantiomer IMP‐1575 , the most potent HHAT inhibitor reported to‐date, and guided design of photocrosslinking probes that maintained HHAT‐inhibitory potency. Photocrosslinking and proteomic sequencing of HHAT delivered identification of the first small‐molecule binding site in a mammalian MBOAT. Topology and homology data suggested a potential mechanism for HHAT inhibition which was confirmed via kinetic analysis. Our results provide an optimal HHAT tool inhibitor IMP‐1575 ( K i = 38 nM) and a strategy for mapping small molecule interaction sites in MBOATs.

  • Journal article
    Kryza T, Khan T, Lovell S, Harrington BS, Yin J, Porazinski S, Pajic M, Koistinen H, Rantala JK, Dreyer T, Magdolen V, Reuning U, He Y, Tate EW, Hooper JDet al., 2021,

    Substrate-biased activity-based probes identify proteases that cleave receptor CDCP1

    , Nature Chemical Biology, Vol: 17, Pages: 776-783, ISSN: 1552-4450

    CUB domain-containing protein 1 (CDCP1) is an oncogenic orphan transmembrane receptor and a promising target for the detection and treatment of cancer. Extracellular proteolysis of CDCP1 by poorly defined mechanisms induces pro-metastatic signaling. We describe a new approach for the rapid identification of proteases responsible for key proteolytic events using a substrate-biased activity-based probe (sbABP) that incorporates a substrate cleavage motif grafted onto a peptidyl diphenyl phosphonate warhead for specific target protease capture, isolation and identification. Using a CDCP1-biased probe, we identify urokinase (uPA) as the master regulator of CDCP1 proteolysis, which acts both by directly cleaving CDCP1 and by activating CDCP1-cleaving plasmin. We show that coexpression of uPA and CDCP1 is strongly predictive of poor disease outcome across multiple cancers and demonstrate that uPA-mediated CDCP1 proteolysis promotes metastasis in disease-relevant preclinical in vivo models. These results highlight CDCP1 cleavage as a potential target to disrupt cancer and establish sbABP technology as a new approach to identify disease-relevant proteases.

  • Journal article
    Tate E, 2021,

    PROTACs, molecular glues and bifunctionals from bench to bedside: Unlocking the clinical potential of catalytic drugs

    , Progress in medicinal chemistry, ISSN: 0079-6468
  • Journal article
    Losada de la Lastra A, Hassan S, Tate EW, 2021,

    Deconvoluting the biology and druggability of protein lipidation using chemical proteomics

    , Current Opinion in Chemical Biology, Vol: 60, Pages: 97-112, ISSN: 1367-5931

    Lipids are indispensable cellular building blocks, and their post-translational attachment to proteins makes them important regulators of many biological processes. Dysfunction of protein lipidation is also implicated in many pathological states, yet its systematic analysis presents significant challenges. Thanks to innovations in chemical proteomics, lipidation can now be readily studied by metabolic tagging using functionalized lipid analogs, enabling global profiling of lipidated substrates using mass spectrometry. This has spearheaded the first deconvolution of their full scope in a range of contexts, from cells to pathogens and multicellular organisms. Protein N-myristoylation, S-acylation, and S-prenylation are the most well-studied lipid post-translational modifications because of their extensive contribution to the regulation of diverse cellular processes. In this review, we focus on recent advances in the study of these post-translational modifications, with an emphasis on how novel mass spectrometry methods have elucidated their roles in fundamental biological processes.

  • Journal article
    Bickel JK, Voisin TB, Tate EW, Bubeck Det al., 2021,

    How Structures of Complement Complexes Guide Therapeutic Design.

    , Subcell Biochem, Vol: 96, Pages: 273-295, ISSN: 0306-0225

    The complement system is essential for immune defence against infection and modulation of proinflammatory responses. Activation of the terminal pathway of complement triggers formation of the membrane attack complex (MAC), a multi-protein pore that punctures membranes. Recent advances in structural biology, specifically cryo-electron microscopy (cryoEM), have provided atomic resolution snapshots along the pore formation pathway. These structures have revealed dramatic conformational rearrangements that enable assembly and membrane rupture. Here we review the structural basis for MAC formation and show how soluble proteins transition into a giant β-barrel pore. We also discuss regulatory complexes of the terminal pathway and their impact on structure-guided drug discovery of complement therapeutics.

  • Journal article
    De Vita E, Maneiro M, Tate EW, 2020,

    The missing link between (Un)druggable and degradable KRAS

    , ACS Central Science, Vol: 6, Pages: 1281-1284, ISSN: 2374-7943

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