Chemical Hijacking of E3 Ligases for the Selective Targeting of Oncogenic mTOR Signaling

ASPIRE Award (2023-Present)

Cristina Mayor-Ruiz, PhD; Antoni Riera Escalé, PhD, Institute for Research in Biomedicine (IRB Barcelona), Spain; Alejo Efeyan, PhD, Centro Nacional de Investigaciones Oncológicas (CNIO), Spain

Cristina Mayor-Ruiz, PhD

Antoni Riera Escalé, PhD

Alejo Efeyan, PhD

mTOR kinase is the key component of two multiprotein complexes: mTORC1 and mTORC2, which regulate essential biological function like cell growth and division. Importantly, more than 30% of tumors show dysregulated activity of the mTOR pathway, with mTORC1 understood to be the critical cancer therapeutic target. While there are existing mTOR inhibitors, the efficacy of current pharmacological agents is limited due to partial allosteric mTORC1 inhibition (rapamycin and analogs), or to the lack of mTORC1 selectivity (ATP-competitive kinase inhibitors). Thus, the selective and efficient targeting of mTORC1 without the severe adverse effects of inhibiting mTORC2 persists as an unmet clinical need.

In this project, Cristina Mayor-Ruiz will lead a team to leverage the immense potential of targeted protein degradation to achieve high levels of selectivity and potency against mTORC1. They will employ a two-pronged approach: develop direct, selective degraders of mTORC1; and identify binders of upstream mTORC1 regulators to indirectly target this complex. These studies could be the first step toward developing novel therapeutic solutions for mTORC1-dependent cancers that have the potential to help tackle the associated unmet clinical need.