Rakovina talks ATR/mTOR dual inhibitor preclinical data

Executive Summary

• Rakovina Therapeutics presented preclinical data at the 2025 Society for Neuro-Oncology (SNO) Annual Meeting regarding its AI-discovered ATR/mTOR dual inhibitors.
• The compounds, developed using the Enki generative AI platform, are designed to penetrate the central nervous system (CNS), addressing a key limitation of current ATR inhibitors.
• Preclinical results show the compounds achieve >50% ATR inhibition at 1 micromolar, exhibit potency comparable to or exceeding leading clinical ATR inhibitors, and demonstrate measurable CNS exposure in mouse models.

Key Details

• Program Focus: Discovery and development of novel CNS-penetrant ATR/mTOR dual inhibitors for PTEN-deficient tumors.
• Technology: Utilized the Enki generative AI platform to design a virtual library of 138 predicted compounds.
• Selection & Synthesis: 43 priority molecules were synthesized for evaluation in biochemical and cellular assays.
• Potency Results:
  • Multiple compounds demonstrated >50% inhibition of recombinant ATR at 1 micromolar.
  • Potency was equal to or greater than leading ATR inhibitors: ceralasertib, tuvusertib, and elimusertib.
  • Maintained similar PIKK-family selectivity.
• Mechanism of Action:
  • Targets ATR (DNA damage response) and mTOR (survival signaling) simultaneously.
  • Designed to overcome resistance mechanisms in PTEN-deficient cancers, which rely on mTOR-driven growth as an escape pathway under ATR inhibition.
  • Specifically engineered to cross the blood-brain barrier for primary brain cancers and cancers with high risk of brain metastasis (e.g., ovarian, lung, breast, melanoma).
• Preclinical Safety & PK:
  • Pharmacokinetic profiling in mice (single 5 mg/kg intraperitoneal dose) showed favorable tolerability.
  • Demonstrated metabolic stability in human liver microsomes.
  • Confirmed measurable CNS exposure, supporting further evaluation in brain tumor models.
• Strategic Context: Collaboration with the Vancouver Prostate Centre for translational capabilities.

Notable Quotes

• "To our knowledge, no company has previously generated a single small-molecule therapeutic designed to combine ATR and mTOR inhibition with CNS penetration. Seeing generative AI propose compounds with this level of precision gives us a fundamentally new way to address these difficult-to-treat cancers with a high risk of brain involvement." — Prof. Mads Daugaard, President and Chief Scientific Officer
• "The reception to our data at SNO has been very encouraging... This program showcases how combining Variational AI's Enki platform with the translational capabilities at the Vancouver Prostate Centre allows us to rapidly pursue differentiated DDR-targeted therapeutics with potential clinical relevance in areas of significant unmet need." — Jeffrey Bacha, Executive Chairman