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• Journal article
  De Vita E, Thomas A, Tate E,

  Discovery of stereoselective targeted covalent inhibitors of the RAB27-effector protein-protein interaction

  , Journal of the American Chemical Society, ISSN: 0002-7863

  RAB27A and RAB27B are homologous small GTPases that regulate intracellular vesicle trafficking, orchestrating endocytic and exocytic processes that affect cellular communication, immune responses, and dynamics of the cellular microenvironment. Through their interactions with effector proteins, RAB27A/B play roles in tumor metastasis and chronic inflammation. However, pharmacological modulation of their activity faces challenges typical of small GTPases, including a lack of well-defined pockets outside the conserved GTP binding site, and large RAB27-effector protein-protein interaction (PPI) surfaces. Here, we present the discovery and development of the first cell-active, rationally designed covalent inhibitors of the RAB27-effector interaction, targeting a non-conserved cysteine residue flanking the PPI interface. An electrophile-first biochemical screen led to a novel class of acrylamide covalent inhibitors, and X-ray crystallography structure-guided design led to optimized inhibitors and probes that enantioselectively target RAB27A/B Cys123 in cells. Potency and selectivity were confirmed through biochemical and cellular assays, including chemical proteomics and phenotype recapitulation in melanocytes alongside a matched inactive enantioprobe control. In contrast, a previously reported compound, Nexinhib-20, was found to be cytotoxic and to exert its activity through non-selective reactivity. This work provides the first toolbox of cell-active chemical probes for RAB27 which can be used in future studies to shed light on the function of this protein and its potential as a therapeutic target.

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• Journal article
  Gray JL, Xiao Z, Rogga VV, Zhang X, Tate EWet al., 2026,
  , J Am Chem Soc, Vol: 148, Pages: 4791-4814

  Molecular glues represent a new paradigm in drug discovery, stabilizing novel protein-protein interactions between two proteins to elicit targeted cellular outcomes. Historically discovered through serendipity, molecular glue identification is becoming increasingly systematic. In this perspective, we discuss the current advances and challenges of this field, highlighting the transition toward rational discovery through the convergence of four complementary approaches. Innovations in library design and screening platforms are expanding access to glue-relevant chemical space, guided by a deeper mechanistic understanding of proximity-induced pharmacology. These efforts are further enabled by functional genomic approaches that reveal gluable interfaces. Finally, the integration of chemical and biological data through machine learning is beginning to support rational de novo glue design.

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• Journal article
  Pérez LR, King TA, Finnigan W, Angelastro A, Cain KM, Eldrid-Otterburn C, Houghton JW, Tate EW, Barran P, Goundry WRF, Flitsch SLet al., 2026,
  , Angew Chem Int Ed Engl, Vol: 65

  The selective modification of proteins and peptides is an important chemical biology tool with a wide variety of applications, including the production of biopharmaceuticals or the study of post-translational modifications. In particular, the selective acylation of the N-terminus over side chains in peptides and proteins is a highly desirable but challenging reaction in this field. Current methods have a range of shortcomings, including lack of selectivity or narrow substrate scope. Here we report a biomimetic approach using the in situ enzymatic reagent activation (ERA) of carboxylic acids with ATP to generate acyl-adenosine monophosphates. This method displays high selectivity for the N-termini of peptides and proteins, including pharmaceutically relevant liraglutide, glucagon and insulin. The ERA acylation tolerates a broad range of unsubstituted and substituted fatty acids, including azido and dicarboxylic acids, thus making it suitable for N-terminal bioorthogonal labelling strategies. Moreover, this strategy can also be applied to the modification of antibodies. In general, the ERA acylation is a versatile and bioorthogonal method that we envisage finding wider applications in the field of bioconjugation and the production of stable peptide and protein conjugates.

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• Journal article
  Lueg G, Zhang J, Faronato M, Gorelik A, Kallemeijn W, Falciani F, Walton J, Houghton J, Vannini S, Poon E, Costa B, Solari R, Carr R, Bell A, Bartlett E, Brzezicha B, Janz M, Chesler L, Calado D, Tate Eet al., 2025,
  , Cell Reports, Vol: 44, ISSN: 2211-1247

  Human N-myristoyltransferases (NMTs) catalyze N-terminal protein N-myristoylation and are promising targets in cancer, with an emerging mechanistic rationale for targeted therapy. Here, we screened 245 cancer cell lines against IMP-1320, a potent NMT inhibitor (NMTi), and conducted pathway-level analyses to identify that deregulated MYC increases cancer cell sensitivity to NMTis. Proteomics on detergent-enriched membrane fractions in MYC or MYCN-deregulated cancer cell models revealed that cell death is associated at least in part with loss of membrane association of mitochondrial respiratory complex I. This is concurrent with loss of myristoylation and degradation of the complex I assembly factor NDUFAF4, and induction of mitochondrial dysfunction, driven by MYC or MYCN-deregulation. NMTis eliminated or suppressed MYC- and MYCN-driven tumors in vivo without overt toxicity, suggesting that this constitutive co-translational protein modification can be targeted in MYC-driven cancers.

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• Journal article
  Gan J, Dabhade P, Wijne C, McKibben W, Draganov SD, Alrawili H, Sun Z-YJ, Houghton JW, Tate EW, Le Gall C, Suresh P, Pishesha N, Pinto-Fernandez A, Schwartz TU, Ploegh HLet al., 2025,
  , JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 301
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• Journal article
  Soday L, Seripracharat C, Gray JL, Luz AFS, Howard RT, Singh R, Burden TJ, Bernardini E, Mateus-Pinheiro M, Petersen J, Gunnarsson A, Gunnarsson J, Aagaard A, Sjögren T, Maslen S, Bartlett EJ, Iles AF, Smith DM, Scott JS, Skehel M, Davis AM, Ressurreição AS, Moreira R, Rodrigues CMP, Shenoy AR, Tate EWet al., 2025,
  , ACS Chemical Biology, Vol: 20, Pages: 1527-1543, ISSN: 1554-8929

  Necroptosis is a form of programmed cell death that, when dysregulated, is associated with cancer and inflammatory and neurodegenerative diseases. Here, starting from hits identified from a phenotypic high-throughput screen for inhibitors of necroptosis, we synthesized a library of compounds containing a 7-phenylquinoline motif and validated their anti-necroptotic activity in a novel live-cell assay. Based on these data, we designed an optimized photoaffinity probe for target engagement studies and through biochemical and cell-based assays established receptor-interacting kinase 1 (RIPK1) as the cellular target, with inhibition of necroptosis arising from the prevention of RIPK1 autophosphorylation and activation. X-ray crystallography and mass spectrometry revealed that these compounds bind at the hinge region of the active conformation of RIPK1, establishing them as type I kinase inhibitors. In addition, we demonstrated in vitro synergy with type III kinase inhibitors, such as necrostatin-1 and found that lead compounds protected mice against acute inflammation in necroptosis models in vivo. Overall, we present a novel pharmacophore for inhibition of human RIPK1, a key protein involved in necroptosis, and provide a photoaffinity probe to explore RIPK1 target engagement in cells.

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• Journal article
  Tate EW, Bickel JK, Ahmed AIS, Pidd AB, Morgan RM, McAllister TE, Horrell SM, Couves EC, Nagaraj H, Bartlett EJ, El Omari K, Kawamura A, Bubeck Det al., 2025,
  , Angewandte Chemie, Vol: 137, ISSN: 0044-8249

  CD59 is an immunomodulatory cell surface receptor associated with human disease. Despite its importance in complement regulation and bacterial pathogenesis, CD59 remains a challenging therapeutic target. Research to date has focused on antibody or protein-based strategies. Here we present a new approach to target CD59 using macrocyclic peptides with low nanomolar affinity for CD59. Through X-ray crystallographic studies and structure-activity relationship (SAR) studies, we identify key interactions that are essential for binding and activity. We find that the macrocyclic peptide CP-06 adopts a beta-hairpin structure and binds CD59 through an intermolecular beta-sheet, mimicking protein–protein interactions of biologically relevant CD59 interaction partners. We create dimeric and lipidated macrocyclic peptide conjugates as enhanced cell-active CD59 inhibitors and show that these probes can be used to modulate both complement-mediated killing of human cells and lytic activity of bacterial virulence factors. Together, our data provide a starting point for future development of macrocyclic peptides to target CD59 activity in diverse cellular contexts.

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• Journal article
  Shchepinova MM, Richardson R, Houghton JW, Walker AR, Safar MA, Conole D, Hanyaloglu AC, Tate EWet al., 2025,
  , Cell Chemical Biology, Vol: 32, Pages: 722-735.e7, ISSN: 2451-9448

  Cellular signaling by membrane G protein-coupled receptors (GPCRs) is governed by a complex and diverse array of mechanisms. The dynamics of a GPCR interactome, as it evolves over time and space in response to an agonist, provide a unique perspective on pleiotropic signaling decoding and functional selectivity at the cellular level. In this study, we utilized proximity-based APEX2 proteomics to investigate the interaction network of the luteinizing hormone receptor (LHR) on a minute-to-minute timescale. We developed an analytical approach that integrates quantitative multiplexed proteomics with temporal reference profiles, creating a platform to identify the proteomic environment of APEX2-tagged LHR at the nanometer scale. LHR activity is finely regulated spatially, leading to the identification of putative interactors, including the Ras-related GTPase RAP2B, which modulate both receptor signaling and post-endocytic trafficking. This work provides a valuable resource for spatiotemporal nanodomain mapping of LHR interactors across subcellular compartments.

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• Journal article
  Date A, Wall A, Zhang P, Houghton J, Lu J, Thomas A, Kovacic T, Wilson A, Tate E, Barnard Aet al., 2025,
  , Chemical Science, Vol: 16, Pages: 6886-6894, ISSN: 2041-6520

  Navtemadlin is a potent inhibitor of the p53-MDM2 protein–protein interaction, which plays a critical role in the proliferation of p53-wildtype tumours. Whilst Navtemadlin has progressed to multiple Phase III clinical trials in oncology, little has been disclosed regarding its selectivity for MDM2 in cells. Here, we report the synthesis and validation of photoactivatable clickable probes of Navtemadlin, and their application to de novo target discovery for Navtemadlin through affinity-based protein profiling. MDM2 was robustly identified as the main target, across two cell lines, using two distinct probe designs. While off-targets were identified, these were not consistent across cell lines and probe designs, consistent with a high degree of selectivity for the target protein. Whole proteome profiling experiments across different time points confirmed p53-mediated phenotypic activity and revealed novel expression patterns for key proteins in the p53 pathway.

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• Journal article
  Mendez A, Bolling C, Taylor S, Makumire S, Staker B, Reers A, Hammerson B, Mayclin SJ, Abendroth J, Lorimer DD, Edwards TE, Tate EW, Subramanian S, Bell AS, Myler PJ, Asojo OA, Chakafana Get al., 2025,
  , Acta Crystallographica Section F: Structural Biology and Crystallization Communications Online, Vol: 81, ISSN: 1744-3091

  Plasmodium vivax is responsible for the most widespread form of malaria and approximately 2.5 billion people, or over one-third of the world's population, are at risk of P. vivax infection (Battle et al., 2019[Battle, K. E., Lucas, T. C. D., Nguyen, M., Howes, R. E., Nandi, A. K., Twohig, K. A., Pfeffer, D. A., Cameron, E., Rao, P. C., Casey, D., Gibson, H. S., Rozier, J. A., Dalrymple, U., Keddie, S. H., Collins, E. L., Harris, J. R., Guerra, C. A., Thorn, M. P., Bisanzio, D., Fullman, N., Huynh, C. K., Kulikoff, X., Kutz, M. J., Lopez, A. D., Mokdad, A. H., Naghavi, M., Nguyen, G., Shackelford, K. A., Vos, T., Wang, H., Lim, S. S., Murray, C. J. L., Price, R. N., Baird, J. K., Smith, D. L., Bhatt, S., Weiss, D. J., Hay, S. I. & Gething, P. W. (2019). Lancet, 394, 332-343.]). In humans, P. vivax can enter a dormant liver phase, which allows it to survive in various climates, including tropical and temperate regions, and contributes to its extensive geographical prevalence (Battle et al., 2019[Battle, K. E., Lucas, T. C. D., Nguyen, M., Howes, R. E., Nandi, A. K., Twohig, K. A., Pfeffer, D. A., Cameron, E., Rao, P. C., Casey, D., Gibson, H. S., Rozier, J. A., Dalrymple, U., Keddie, S. H., Collins, E. L., Harris, J. R., Guerra, C. A., Thorn, M. P., Bisanzio, D., Fullman, N., Huynh, C. K., Kulikoff, X., Kutz, M. J., Lopez, A. D., Mokdad, A. H., Naghavi, M., Nguyen, G., Shackelford, K. A., Vos, T., Wang, H., Lim, S. S., Murray, C. J. L., Price, R. N., Baird, J. K., Smith, D. L., Bhatt, S., Weiss, D. J., Hay, S. I. & Gething, P. W. (2019). Lancet, 394, 332-343.]). P. vivax infection significantly impacts the quality of life of infected individuals, causing cyclical episodes of fever and weakness, representing a substantial burden in endemic countries due to treatment costs and productivity loss. P. vivax can persist in human hosts as hypnozoites in the liver that can cause relapses that can extend over several months or years (Flannery et al., 2022[Flannery, E.

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