Enhanced Potential of Myricx’s NMT Inhibitor Payloads with Dual Senolytic and Cytotoxic Modes of Action as ADC Cancer Therapies

Scientists Uncover Central Role of N-Myristoylation in Senescence

• Data published today in Nature Cell Biology by Myricx collaborators at the MRC-LMS (Laboratory of Medical Sciences) led by Prof. Jesús Gil have uncovered the central role of N-myristoyltransferase (NMT) as a druggable pathway in senescence

• Myricx’s proprietary NMT inhibitors (NMTis) were shown to have a potent senolytic effect, selectively eliminating senescent non-dividing cells

• Clear differentiation for Myricx’s NMTi proprietary payloads for antibody-drug conjugates (ADCs) with dual senolytic as well as cytotoxic MOA has the potential to induce deeper and more durable tumour responses 
• Myricx has licensed exclusive IP rights to develop NMTis for senescence applications from Imperial College Innovations Limited and UKRI

London, UK 27 November 2023 – Myricx Bio (‘Myricx’), a UK biotech company focused on the discovery and development of a completely novel class of antibody-drug conjugate (ADC) payloads based on N-Myristoyltransferase (NMT) inhibition, is pleased to announce the publication today of ground-breaking research in Nature Cell Biology¹ by its collaborators at the MRC-LMS (Laboratory of Medical Sciences) that has uncovered the central role of NMT as a druggable pathway in senescence.

Cellular senescence, the process when cells stop dividing and undergo distinct physiological changes is implicated in many diseases. Senescent or so called ‘zombie’ cells can have deleterious effects on tissue function as they are persistent and secrete many proteins. In tumours, these proteins can drive chronic inflammation, metastasis, drug resistance and tumour growth. Small-molecule drugs that selectively eliminate senescent cells, known as senolytics, provide a promising novel strategy for treating multiple diseases, including cancer, fibrotic diseases, and age-related conditions.

The research, funded by UKRI MRC and CRUK, involved a major collaborative study led by Myricx’s Scientific Consultant and Collaborator, Professor Jesús Gil, lead author of the study and Head of the Senescence Research Group at MRC-LMS, together with Myricx co-founder Professor Ed Tate, and 18 other scientists, discovered that small molecule NMTis can selectively kill senescent cancer cells.

Overall, the study demonstrated that senescent cells rely on a hyperactive secretory apparatus and that this secretory phenotype is dependent on NMT and inhibiting NMT kills senescent cells. This discovery opens up the potential to treat various senescence-associated diseases with NMTis, including cancer.

At a more detailed cellular level, this study demonstrated that coatomer complex I (COPI) vesicle formation in senescent cells is a process (vulnerability/liability) that can be targeted with COPI inhibitors, however these senolytic drugs have poor pharmacological properties. Compelling data then showed that Myricx’s proprietary potent NMTis are non-toxic senolytics that mirror the effects of (phenocopy) COPI inhibition by selectively eliminating senescent cells with improved outcomes in different in vivo proof-of-concept cancer models. Specifically, NMTi targets ARF1, a key regulator of COPI vesicle formation that needs a lipid modification (called myristoylation) to be functional.

Professor Jesús Gil, MRC Laboratory of Medical Sciences, and Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London added, “Our team has long been looking into senolytic targets that effectively and selectively kill senescent cells. In a previous study, we showed the potential of repurposing existing drugs, but there are only limited drugs to choose from. In this study, we expanded our selection pool to be much larger by seeking targets in over 7,000 ‘druggable’ genes. We were thrilled to reveal previously unknown vulnerabilities of senescent cells. This opens up new possibilities for treating age-related diseases and cancer.

“A big part of the success of the project was thanks to the close collaboration with Ed Tate’s lab and all of the Myricx team. Roberto Solari, a Myricx Bio co-founder, was always there to give advice and see how we could push the project forward.”

Prof Ed Tate, Myricx co-founder and Chair of its Scientific Advisory Board, and GSK Chair of Chemical Biology at Imperial College London and a Satellite Group Leader at the Francis Crick Institute said, "Our findings suggest that NMT inhibition could be a game-changer in senolytic therapy. Our potent, selective, in vivo active small molecule NMTis open exciting avenues for further research and development, as the first senolytic targeting protein lipidation.”

CEO of Myricx BIO, Dr Robin Carr said, “The senolytic properties that this research has demonstrated gives our NMTi-ADCs the potential for a highly differentiated profile not addressed by any other ADCs. Combined with the cytotoxic effect of NMTis, the senolytic mechanism has the potential to induce deeper and more durable responses in treating tumours than purely cytotoxic payloads. We look forward to exploring this as we advance our drugs into clinical trials.”     

Myricx has patents pending and licensed exclusive IP rights to develop NMTis as novel drugs including in senescence applications from Imperial College Innovations Limited and UKRI. The company has validated its NMTi payload platform having demonstrated in vivo pre-clinical efficacy for three NMTi-ADCs in its pipeline (B7-H3-NMTi, TROP2-NMTi, HER2-NMTi) showing complete and durable tumour regressions in multiple cancer models.

• 1. COPI vesicle formation and N-myristoylation are targetable vulnerabilities of senescent cell, Nature Cell Biology, 27 November 2023 - nature.com/articles/s41556-023-01287-6