A novel brain-penetrant dual ATR-mTOR inhibitor for PTEN-deficient cancers

Ataxia telangiectasia and Rad3-related protein serine/threonine kinase (ATR), a master regulator of DNA damage repair, maintains genomic stability in cancer cells and allows cancer cells to survive with high replication stress. Inhibition of ATR thus causes genomic instability, leading to mitotic catastrophe and apoptosis. ATR inhibitors (ATRi) have been found to be particularly effective against cells harboring PTEN deficiencies due to synthetic lethality. PTEN regulates the cell cycle and interacts with key proteins like p53 and Chk1, and PTEN deficient cells show increased genomic instability due to compromised DNA repair. Inhibition of ATR in PTEN-deficient cells therefore leads to accumulation of DNA damage and cell death. PTEN loss/mutation also leads to activation of mTOR through activation of PDK1 and AKT, contributing to cell survival and growth. Therefore, simultaneous inhibition of ATR and mTOR seems rational in the context of PTEN-deficient tumor cells. PTEN deficiency can be found in up to 40% of gliomas and 63% of breast cancers, which often metastasize to the brain. Since combination treatments can be clinically difficult due to overlapping toxicities and differing pharmacokinetics, we sought to develop a CNS-penetrating dual inhibitor of ATR and mTOR for the treatment of PTEN-deficient cancers. A generative artificial intelligence platform called Enki™ was used to identify de novo molecules with optimized properties for CNS penetrance and specificity for ATR and mTOR. Enki uses a latent diffusion model to optimize many properties simultaneously within the search space, including maximal potency against the primary target, selectivity, ADMET, and physicochemical properties. The most promising molecules were synthesized and tested, and data on potency, selectivity, ADME and in vivo efficacy will be presented. Enki™ has enabled deep exploration of chemical space and rapid generation of de novo molecules, accelerating the drug discovery process and allowing discovery and development of CNS-penetrating dual ATR and mTOR inhibitors.