MYC deregulation sensitizes cancer cells to N-myristoyltransferase inhibition

Gregor A Lueg¹, James Zhang², Monica Faronato¹, Andrii Gorelik¹, Wouter W Kallemeijn¹, Francesco Falciani³, Josephine Walton⁴, Jack W Houghton⁵, Silvia Vannini⁵, Evon Poon⁶, Barbara M Costa⁶, Roberto Solari³, Robin Carr³, Andrew S Bell⁴, Edward J Bartlett⁵, Bernadette Brzezicha⁷, Martin Janz⁸, Louis Chesler⁶, Dinis P Calado⁹, Edward W Tate¹⁰

Affiliations

¹ Department of Chemistry, Molecular Sciences Research Hub, White City Campus, Imperial College London, 82 Wood Lane, W12 0BZ London, UK; The Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK.
² Department of Chemistry, Molecular Sciences Research Hub, White City Campus, Imperial College London, 82 Wood Lane, W12 0BZ London, UK; The Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK; Division of Clinical Studies, The Institute of Cancer Research (ICR) & Royal Marsden NHS Trust, SW3 6JB London, UK.
³ Myricx Pharma Limited, London Innovation Centre, 20 Water Street, E14 5GX London, UK.
⁴ Department of Chemistry, Molecular Sciences Research Hub, White City Campus, Imperial College London, 82 Wood Lane, W12 0BZ London, UK; Myricx Pharma Limited, London Innovation Centre, 20 Water Street, E14 5GX London, UK.
⁵ Department of Chemistry, Molecular Sciences Research Hub, White City Campus, Imperial College London, 82 Wood Lane, W12 0BZ London, UK.
⁶ Division of Clinical Studies, The Institute of Cancer Research (ICR) & Royal Marsden NHS Trust, SW3 6JB London, UK.
⁷ Experimental Pharmacology & Oncology Berlin-Buch, Robert-Rössle-Str. 10, 13125 Berlin, Germany.
⁸ Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité - Universitätsmedizin Berlin, 13125 Berlin, Germany.
⁹ The Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK; Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, The Francis Crick, SE1 9RT London, UK. Electronic address: dinis.calado@crick.ac.uk.
¹⁰ Department of Chemistry, Molecular Sciences Research Hub, White City Campus, Imperial College London, 82 Wood Lane, W12 0BZ London, UK; The Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK; Myricx Pharma Limited, London Innovation Centre, 20 Water Street, E14 5GX London, UK. Electronic address: e.tate@imperial.ac.uk.

PMID: 40849903
DOI: 10.1016/j.celrep.2025.116180

Free article

MYC deregulation sensitizes cancer cells to N-myristoyltransferase inhibition

Gregor A Lueg et al. Cell Rep. 2025.

Free article

. 2025 Sep 23;44(9):116180.

doi: 10.1016/j.celrep.2025.116180. Epub 2025 Aug 22.

Authors

Affiliations

¹ Department of Chemistry, Molecular Sciences Research Hub, White City Campus, Imperial College London, 82 Wood Lane, W12 0BZ London, UK; The Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK.
² Department of Chemistry, Molecular Sciences Research Hub, White City Campus, Imperial College London, 82 Wood Lane, W12 0BZ London, UK; The Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK; Division of Clinical Studies, The Institute of Cancer Research (ICR) & Royal Marsden NHS Trust, SW3 6JB London, UK.
³ Myricx Pharma Limited, London Innovation Centre, 20 Water Street, E14 5GX London, UK.
⁴ Department of Chemistry, Molecular Sciences Research Hub, White City Campus, Imperial College London, 82 Wood Lane, W12 0BZ London, UK; Myricx Pharma Limited, London Innovation Centre, 20 Water Street, E14 5GX London, UK.
⁵ Department of Chemistry, Molecular Sciences Research Hub, White City Campus, Imperial College London, 82 Wood Lane, W12 0BZ London, UK.
⁶ Division of Clinical Studies, The Institute of Cancer Research (ICR) & Royal Marsden NHS Trust, SW3 6JB London, UK.
⁷ Experimental Pharmacology & Oncology Berlin-Buch, Robert-Rössle-Str. 10, 13125 Berlin, Germany.
⁸ Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité - Universitätsmedizin Berlin, 13125 Berlin, Germany.
⁹ The Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK; Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, The Francis Crick, SE1 9RT London, UK. Electronic address: dinis.calado@crick.ac.uk.
¹⁰ Department of Chemistry, Molecular Sciences Research Hub, White City Campus, Imperial College London, 82 Wood Lane, W12 0BZ London, UK; The Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK; Myricx Pharma Limited, London Innovation Centre, 20 Water Street, E14 5GX London, UK. Electronic address: e.tate@imperial.ac.uk.

PMID: 40849903
DOI: 10.1016/j.celrep.2025.116180

Abstract

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.

Keywords: CP: Cancer; CP: Molecular biology; Complex I; MYC; MYCN; N-myristoylation; N-myristoyltransferase; NDUFAF4; NMT.

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Conflict of interest statement

Declaration of interests E.W.T., A.S.B., R.S., and M.F. are founders and shareholders of Myricx Pharma Ltd; R.C. is an employee and shareholder; J.W. is an employee; and E.W.T., R.S., A.S.B., and F.F. are consultants of the company, which holds licences to patents covering the composition and use of N-myristoyltransferase (NMT) inhibitors. E.W.T., A.S.B., D.P.C., G.A.L., R.S., R.C., and M.F. are named as inventors on patents relating to NMT inhibitors (WO2017001812A1, US2020/0339586, WO2020128473, and WO2024052685), synthetic lethality of NMT inhibitors in high-MYC cancers (WO2020128475), and the use of NMT inhibitors as ADC payloads (WO2024052684A1). The authors declare no other relevant competing interests.

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MYC deregulation sensitizes cancer cells to N-myristoyltransferase inhibition

Affiliations

MYC deregulation sensitizes cancer cells to N-myristoyltransferase inhibition

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous