PI Kostas Tzelepis presents at the 65th Annual ASH Conference on STORM Therapeutics’ First-in-Class tRNA methyltransferase inhibitor

On Friday 8 December, CSCI PI Kostantinos Tzelepis presented his research at the Annual American Society of Hematology (ASH) Meeting in San Diego, USA.

This presentation focused on the pre-clinical development and characterisation of the first-in-class METTL1 RNA Methyltransferase inhibitor, a totally novel anticancer therapeutic for various aggressive malignancies including AML and melanoma. This effort capitalises on the previous collaborative work from the Tzelepis group that revealed METTL1 as an important vulnerability for a number of aggressive malignancies (Orellana et al, Molecular Cell 2021).

This novel and ongoing translational work is a collaborative effort with STORM Therapeutics Ltd (STORM), the clinical stage biotechnology company discovering and developing novel small molecule therapies targeting RNA modifying enzymes (RMEs) for oncology and other diseases.

The presentation, entitled “Overcoming Therapy Resistance in AML Using Novel Epitranscriptomic Modalities” detailed results showing that pharmacological inhibition of a tRNA methyltransferase affects tumor growth in in vitro and humanized in vivo models.

 Preclinical data demonstrated that:

1. STORM METTL1 inhibitors exhibit METTL1 inhibition in vitro at low nanomolar concentrations while displaying high selectivity over other RNA and protein methyltransferases.
2. Mechanistically, METTL1 inhibition leads to reduced tRNA methylation and reduced stability of a subgroup of tRNAs.
3. In several cancer models, METTL1 inhibition impairs cell proliferation and cell cycle progression accompanied by elevation of differentiation markers.
4. In vivo, METTL1i treatment induced strong tumour growth inhibition in a number of cell-line derived xenografts and syngeneic in vivo cancer studies (haematological and solid malignancies), using both immune-deficient and immune-competent strains.

Kostas Tzelepis, Principal Investigator at the Cambridge Stem Cell Institute, says:

“We are very excited to present novel data on the development and characterisation of the first-in-class bioavailable tRNA methyltransferase inhibitor against METTL1. This is a fantastic collaborative effort which expands significantly the therapeutic landscape of the epitranscriptomics field and capitalises on our previous published work which shown that METTL1 is a key player in oncogenesis.”

Jerry McMahon, Chief Executive Officer & President of STORM Therapeutics, said: “It is very exciting to be able to share data on our METTL1 inhibitor for the first time at the prestigious ASH Meeting, 2023. The data are extremely encouraging demonstrating METTL1 inhibition is efficacious and selective and leads to strong anti-cancer effect. We look forward to advancing our first-in-class METTL1 program into the clinic.”