Superpotent, superselective mTOR inhibitors

Application

Treatment of solid and blood cancers, metabolic disorders, fibrosis, ageing, neurodegenerative disorders and other immune-related diseases.

Development Status

Undergoing preclinical development in state-of-the-art cancer models

IP Status

PCT/GB2025/052680 filed December 2025

Commercial Offering

Licence opportunity

Opportunity

Mechanistic Target Of Rapamycin (mTOR), a Serine/Threonine kinase, is a master regulator of key oncogenic processes central to cancer, including cell migration (responsible for metastases), protein synthesis and cell proliferation. mTOR exerts its effects as a core unit of two multimeric protein complexes, mTORC1 and mTORC2, which are both highly implicated in haematologicaland solid cancers. In addition, the role of mTOR is well established in other pathologies such as ageing, fibrosis, metabolic and neurodegenerative disorders, and immune-related diseases, opening up opportunities for therapeutic intervention in these indications.

The patented set of drug candidates displays superb inhibition of mTOR kinase activity. Thus, unlike rapalogs which only inhibit the mTORC1 complex, the novel drugs disrupt both mTORC1 and mTORC2. These molecules are currently in pre-clinical development with efficacy obtained in cancer models in vivo. The University of Edinburgh is looking for a partner with the experience and capital to progress this IP towards IND-enabling studies and clinical trials.

Technology

The novel inhibitors display sub-nanomolar IC₅₀ values both in biochemical assays and in cell culture (Fig 1). Notably, at 1 μM, full kinome profiling (364 kinases) shows that the compounds inhibit 50 % of the enzymatic activity of less than 10 kinases (Fig 2). The lead compound, eALM1396 is >50-fold less potent against the second-most inhibited kinase in the panel (the PIKK family member DNA-PK) and features optimal PK properties in murine models, including excellent oral bioavailability (>70%).

Once daily administration of eALM1396 (2.5, 5, and 10mg/kg) to mice bearing SW48 xenografts resulted in total inhibition of mTOR activity. pAKT Ser473 was used as readout for mTORC2 activity inhibition in these models (Fig3b). Similar results were obtained using the SW48 cell line in culture where the phosphorylation of AKT on Ser473 was fully inhibited at concentrations above 1nM (Fig3a).

In vivo, eALM1396 induced a dose-dependent reduction of tumour growth in an SW48 Xenograft model, achieving >70% TGI at day 14 of treatment by once daily oral dosing (Fig 4). The results correlated with the reduced cell proliferation observed in vitro for this model.

As the rapalog everolimus is approved in combination with chemotherapy (exemestane) to treat ER+ breast cancer, eALM1396 was also tested in an ER+ breast cancer xenograft model in vivo. Once daily oral dosing of male SCID Mice bearing MCF7 xenograft ER+ breast cancer cells resulted in tumour regression (Fig 5, 14 % tumour reduction compared to tumour size at day 0).

Benefits

• Highly potent mTOR kinase inhibition
• Inhibition of both mTORC1 and mTORC2 complexes, circumventing the limitations of rapalogs
• Superselectivity over the rest of the kinome, offering potential superior tolerability for medical treatment than current less selective kinase inhibitors that inhibit mTOR
• Excellent in vivo PK properties
• Efficacy validated in cancer models in vivo

Publications

Over 20 analogues, which are more potent and selective than Sapanisertib, have been discovered and patented. Early examples include the tool compound eALM1137, which was shown to strongly suppress Glioblastoma Multiform Cell growth recently published in J Med Chem.

Álvaro Lorente-Macias, Jonathon Mok, John C. Dawson, Ana Juan-Albuquerque, Neil O. Carragher, Margaret C. Frame, and Asier Unciti-Broceta. Discovery of a Highly Potent and Selective mTOR Inhibitor that Strongly Suppresses Glioblastoma Multiforme Cell Growth. Journal of Medicinal Chemistry 2026, 69, 8, 9680-9712

Quote: TEC1104782