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Journal articleGray JL, Xiao Z, Rogga VV, et al., 2026,
From Serendipity to Strategy: Rationalizing Molecular Glue Discovery and Proximity-Induced Pharmacology through Chemical Biology.
, J Am Chem Soc, Vol: 148, Pages: 4791-4814Molecular 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 articlePérez LR, King TA, Finnigan W, et al., 2026,
Selective N-Terminal Modification of Peptides and Proteins Using Fatty Acyl Phosphates.
, Angew Chem Int Ed Engl, Vol: 65The 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 articleLueg G, Zhang J, Faronato M, et al., 2025,
MYC deregulation sensitizes cancer cells to N-myristoyltransferase inhibition
, Cell Reports, Vol: 44, ISSN: 2211-1247Human 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 articleGan J, Dabhade P, Wijne C, et al., 2025,
Identification and characterization of nanobodies specific for the human ubiquitin-like ISG15 protein
, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 301 -
Journal articleSoday L, Seripracharat C, Gray JL, et al., 2025,
Discovery and validation of a novel class of necroptosis inhibitors targeting RIPK1
, ACS Chemical Biology, Vol: 20, Pages: 1527-1543, ISSN: 1554-8929Necroptosis 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 articleTate EW, Bickel JK, Ahmed AIS, et al., 2025,
Macrocyclic peptide probes for immunomodulatory protein CD59: potent modulators of bacterial toxin activity and antibody-dependent cytotoxicity
, Angewandte Chemie, Vol: 137, ISSN: 0044-8249CD59 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 articleShchepinova MM, Richardson R, Houghton JW, et al., 2025,
Spatiotemporally resolved GPCR interactome uncovers unique mediators of receptor agonism
, Cell Chemical Biology, Vol: 32, Pages: 722-735.e7, ISSN: 2451-9448Cellular 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 articleDate A, Wall A, Zhang P, et al., 2025,
Affinity-based protein profiling of MDM2 inhibitor Navtemadlin
, Chemical Science, Vol: 16, Pages: 6886-6894, ISSN: 2041-6520Navtemadlin 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 articleMendez A, Bolling C, Taylor S, et al., 2025,
Structure of Plasmodium vivax N-myristoyltransferase with inhibitor IMP-1088: exploring an NMT inhibitor for antimalarial therapy
, Acta Crystallographica Section F: Structural Biology and Crystallization Communications Online, Vol: 81, ISSN: 1744-3091Plasmodium 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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Journal articleZhang J, Kallemeijn WW, Hassan S, et al., 2025,
Chemical proteomic approaches to investigate N-myristoylation.
, Methods Enzymol, Vol: 718, Pages: 215-240The protein lipidation event N-myristoylation is catalyzed by the N-myristoyltransferase (NMT) enzymes and occurs on over 200 proteins with N-terminal glycines. The modification controls the localization, stability, function and interactions of its substrate proteins and has been implicated in the regulation of multiple biological processes and disease pathologies. Understanding how the N-myristoylated proteome is altered in these pathologies and in response to pharmacological NMT inhibition is therefore critical to understand how N-myristoylation regulates basic biology and how its pharmacological inhibition may be optimally leveraged in clinical settings. Chemical proteomic approaches have emerged as powerful methods to profile protein post-translational modifications, including lipidation, on a proteome-wide scale. This chapter describes two complementary chemical proteomic methods to assess N-myristoylation. The metabolic labelling approach is based on the uptake and incorporation of bio-orthogonal myristic acid analogues into NMT substrates, allowing the selective labelling, enrichment and detection of these proteins. In contrast, the second method is based on the ability of Sortase A to modify N-terminal glycines with a substrate peptide, allowing the incorporation of an enrichment handle in NMT substrates lacking N-myristoylation, for example due to pharmacological NMT inhibition. Detailed, up-to-date protocols for both chemical proteomic approaches are described in this chapter and encompass all steps of the workflows, including cell treatment, sample preparation and data analysis.
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Contact
Prof. Ed Tate
GSK Chair in Chemical Biology
Department of Chemistry
Molecular Sciences Research Hub, White City Campus,
82 Wood Lane, London, W12 0BZ
e.tate@imperial.ac.uk
Tel: +44 (0)20 759 + ext 43752 or 45821