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Journal articleKryza T, Khan T, Lovell S, et al., 2021,
Substrate-biased activity-based probes identify proteases that cleave receptor CDCP1
, Nature Chemical Biology, Vol: 17, Pages: 776-783, ISSN: 1552-4450CUB 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.
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Journal articleLosada 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: 1367-5931Lipids 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.
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Journal articleBickel JK, Voisin TB, Tate EW, et al., 2021,
How Structures of Complement Complexes Guide Therapeutic Design.
, Subcell Biochem, Vol: 96, Pages: 273-295, ISSN: 0306-0225The 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.
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Journal articleDe 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 -
Journal articleBenns HJ, Wincott CJ, Tate EW, et al., 2020,
Activity- and reactivity-based proteomics: Recent technological advances and applications in drug discovery.
, Current Opinion in Chemical Biology, Vol: 60, Pages: 20-29, ISSN: 1367-5931Activity-based protein profiling (ABPP) is recognized as a powerful and versatile chemoproteomic technology in drug discovery. Central to ABPP is the use of activity-based probes to report the activity of specific enzymes or reactivity of amino acid types in complex biological systems. Over the last two decades, ABPP has facilitated the identification of new drug targets and discovery of lead compounds in human and infectious disease. Furthermore, as part of a sustained global effort to illuminate the druggable proteome, the repertoire of target classes addressable with activity-based probes has vastly expanded in recent years. Here, we provide an overview of ABPP and summarise the major technological advances with an emphasis on probe development.
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Journal articleBell AS, Yu Z, Hutton JA, et al., 2020,
Novel thienopyrimidine inhibitors of Leishmania N-myristoyltransferase with on-target activity in intracellular amastigotes
, Journal of Medicinal Chemistry, Vol: 14, Pages: 7740-7765, ISSN: 0022-2623The leishmaniases, caused by Leishmania species of protozoan parasites, are neglected tropical diseases with 12-15 million cases worldwide. Current therapeutic approaches are limited by toxicity, resistance and cost. N-Myristoyltransferase (NMT), an enzyme ubiquitous and essential in all eukaryotes, has been validated via genetic and pharmacological methods as a promising antileishmanial target. Here we describe a comprehensive structure activity relationship study of a thienopyrimidine series previously identified in a high throughput screen against Leishmania NMT, across 68 compounds in enzyme- and cell-based assay formats. Using a chemical tagging target engagement biomarker assay we identify the first inhibitor in this series with on-target NMT activity in leishmania parasites. Furthermore, crystal structure analyses of 12 derivatives in complex with Leishmania major NMT revealed key factors important for future structure-guided optimization delivering IMP-105 (43), a compound with modest activity against L. donovani intracellular amastigotes and excellent selectivity (>660-fold) for Leishmania NMT over human NMTs.
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Journal articlePanyain N, Godinat A, Lanyon-Hogg T, et al., 2020,
Discovery of a potent and selective covalent inhibitor and activity-based probe for the deubiquitylating enzyme UCHL1, with anti-fibrotic activity
, Journal of the American Chemical Society, Vol: 142, Pages: 12020-12026, ISSN: 0002-7863Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a deubiquitylating enzyme which is proposed as a potential therapeutic target in neurodegeneration, cancer, and liver and lung fibrosis. Herein we report the discovery of the most potent and selective UCHL1 probe (IMP-1710) to date based on a covalent inhibitor scaffold and apply this probe to identify and quantify target proteins in intact human cells. IMP-1710 stereoselectively labels the catalytic cysteine of UCHL1 at low nanomolar concentration in cells. We further demonstrate that potent and selective UCHL1 inhibitors block pro-fibrotic responses in a cellular model of idiopathic pulmonary fibrosis, supporting the potential of UCHL1 as a potential therapeutic target in fibrotic diseases.
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Journal articleAlzahofi N, Welz T, Robinson CL, et al., 2020,
Rab27a co-ordinates actin-dependent transport by controlling organelle-associated motors and track assembly proteins
, NATURE COMMUNICATIONS, Vol: 11, ISSN: 2041-1723- Author Web Link
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- Citations: 12
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Journal articleBroncel M, Dominicus C, Vigetti L, et al., 2020,
Profiling of myristoylation in Toxoplasma gondii reveals an N-myristoylated protein important for host cell penetration
, ELIFE, Vol: 9, ISSN: 2050-084X- Author Web Link
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- Citations: 6
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Journal articleManeiro M, Forte N, Shchepinova MM, et al., 2020,
Antibody–PROTAC conjugates enable HER2-dependent targeted protein degradation of BRD4
, ACS Chemical Biology, Vol: 15, Pages: 1306-1312, ISSN: 1554-8929Targeting protein degradation with Proteolysis-Targeting Chimeras (PROTACs) is an area of great current interest in drug discovery. Nevertheless, although the high effectiveness of PROTACs against a wide variety of targets has been established, most degraders reported to date display limited intrinsic tissue selectivity and do not discriminate between cells of different types. Here, we describe a strategy for selective protein degradation in a specific cell type. We report the design and synthesis of a trastuzumab-PROTAC conjugate (Ab-PROTAC 3) in which E3 ligase-directed degrader activity is caged with an antibody linker which can be hydrolyzed following antibody–PROTAC internalization, releasing the active PROTAC and inducing catalytic protein degradation. We show that 3 selectively targets bromodomain-containing protein 4 (BRD4) for degradation only in HER2 positive breast cancer cell lines, while sparing HER2 negative cells. Using live cell confocal microscopy, we show internalization and lysosomal trafficking of the conjugate specifically in HER2 positive cells, leading to the release of active PROTAC in quantities sufficient to induce potent BRD4 degradation. These studies demonstrate proof-of-concept for tissue-specific BRD4 degradation, overcoming limitations of PROTAC selectivity, with significant potential for application to novel targets.
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