Abstract C085: Discovery and Preclinical Development of Best-in-Class Superpotent Superselective mTOR Inhibitors for Cancer Treatment

Abstract Background: The serine/threonine kinase mTOR is a master regulator of signaling pathways central to cancer. mTOR mediates its effect by forming two multiprotein complexes: (i) mTORC1, which regulates cellular growth and metabolism; and (ii) mTORC2, which controls cell proliferation, survival and migration. The first generation of drugs discovered to inhibit mTOR-associated pathways were large macrocyclic compounds known as rapalogs. Besides their poor pharmacokinetic properties (e.g., low oral bioavailability), the fundamental limitation of these drugs —approved for breast cancer— is that they only inhibit the mTORC1 complex, leading to compensatory activation through mTORC2, significantly reducing drug efficacy. This is the Achilles heel of rapalogs. To fully block mTOR signaling, simultaneous inhibition of mTORC1 and mTORC2 is necessary. Drugs that inhibit the kinase activity of mTOR, the catalytic unit of both complexes, could solve the shortcomings of rapalogs. However, current mTOR kinase inhibitors (second generation) display high promiscuity and insufficient in vivo activity, limiting their efficiency and tolerability. Objectives and Research Strategy: To address the limitations of current inhibitors of the mTOR pathway, we aimed to develop superpotent superselective mTOR kinase inhibitors. Following a ligand-based rational design, the novel inhibitors were developed by iterative synthesis, screening against cancer cell lines and redesign. Kinome screens were conducted in parallel to assess selectivity of novel compounds, followed by in vitro and in vivo DMPK-Tox studies. The activity of the lead compounds was fully characterized by immunoblotting, multi-omics studies and animal models. Results: We have discovered a unique family of small molecule inhibitors with unprecedented potency and selectivity for mTOR kinase. These novel anticancer drug candidates display higher potency against cancer cells —including colorectal and breast cancer cell lines— than any other mTOR inhibitor reported to date. Western blot showed selective inhibition of mTORC1 and mTORC2 substrates in the subnanomolar range. To the best of our knowledge, this level of activity has never been shown before. Conclusions: Our novel patented mTOR inhibitors not only outclass every existing mTOR inhibitor in terms of potency but also display super-selectivity for mTOR kinase. This can not only improve tolerability but also efficacy, as many promiscuous inhibitors also block kinases that negatively regulate mTOR signaling, causing reactivation. Excitingly, our lead candidate shows excellent in vitro and in vivo drug-like properties, including high oral bioavailability and lack of toxic liabilities, making it the optimal drug candidate to fulfil the therapeutic potential of mTOR inhibitors in the clinic. References [1] Lorente-Macías, A., Mok, J., Frame, M. and Unciti-Broceta, A.: ‘Inhibitor compounds’. Application filed UK No. GB2418176.0 Citation Format: Álvaro Lorente-Macias, Jonathon Mok, Margaret C. Frame, Asier Unciti-Broceta. Discovery and Preclinical Development of Best-in-Class Superpotent Superselective mTOR Inhibitors for Cancer Treatment [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C085.