Rakovina talks ATR/mTOR dual inhibitor preclinical data

Mr. Jeffrey Bacha reports RAKOVINA THERAPEUTICS SHOWCASES COMPELLING PRECLINICAL DATA ON AI-DISCOVERED CNS-PENETRANT ATR/MTOR INHIBITORS AT THE 2025 SOCIETY FOR NEURO-ONCOLOGY ANNUAL MEETING Rakovina Therapeutics Inc. has released impressive results from its AI-enabled (artificial intelligence) ATR program at the 2025 Society for Neuro-Oncology (SNO) annual meeting, which took place Nov. 19 to 23 in Honolulu, Hawaii. The poster, titled "Discovery and development of a novel CNS-penetrating ATR inhibitor: Dual inhibition of ATR and mTOR in PTEN-deficient tumours," highlights the discovery and early characterization of novel ATR/mTOR dual inhibitors designed using the Enki generative AI platform. The compounds are engineered to modulate two well-established cancer-driving pathways that, despite their importance, have never before been combined in a single therapeutic agent. Notably, Rakovina's lead molecules were designed specifically to cross the blood-brain barrier and reach tumour cells within the central nervous system, supporting their potential relevance in primary brain cancers and cancers with a high risk of brain metastasis. Rakovina's senior management team presented the findings showing that the AI-discovered ATR+mTOR inhibitors achieve meaningful CNS (central nervous system) penetration, addressing a key limitation of current clinical ATR inhibitors, which have poor CNS distribution. In direct comparisons, multiple Rakovina compounds showed greater-than-50-per-cent ATR inhibition at one micromolar and exhibited equal or greater enzymatic potency than leading ATR inhibitors ceralasertib, tuvusertib and elimusertib while maintaining similar PIKK-family selectivity. Importantly, these compounds were engineered with a mechanistic rationale to co-target ATR and mTOR, two pathways on which PTEN-deficient tumours (including those prone to brain metastasis) are highly dependent. By simultaneously blocking ATR-mediated DNA damage response and mTOR-driven survival signalling, these CNS-penetrant inhibitors have the potential to overcome key resistance mechanisms in PTEN-deficient cancers and deliver therapeutic effects not achievable with ATR-only agents. PTEN deficiency in cancer PTEN is one of the most frequently lost tumour-suppressor genes in human cancer and serves as a key brake on the PI3K/AKT/mTOR signalling pathway that governs cell growth, metabolism and survival. Its loss promotes unchecked proliferation, genomic instability, therapy resistance and aggressive tumour progression. PTEN deficiency is particularly prevalent in cancers with a high propensity for CNS spread, including ovarian, lung, breast and melanoma -- where tumour cells rely heavily on mTOR-driven growth and survival. In these settings, mTOR becomes an adaptive escape pathway, especially under ATR inhibition, allowing PTEN-deficient tumours to accelerate growth and diminish the effectiveness of ATR-only therapeutic strategies. Using the Enki generative AI platform, the company designed a virtual library of 138 predicted compounds, from which 43 priority molecules were synthesized for evaluation in biochemical and cellular assays. Multiple compounds demonstrated greater-than-50-per-cent inhibition of recombinant ATR at one micromolar and exhibited potency comparable with or exceeding ATR inhibitors currently in development, including ceralasertib, tuvusertib and elimusertib. Pharmacokinetic profiling in mice following a single five-milligram-per-kilogram intraperitoneal dose revealed favourable tolerability, metabolic stability in human liver microsomes and measurable CNS exposure, supporting further evaluation in brain tumour models. "Sharing these data at SNO is an important milestone for our ATR/mTOR program," said Prof. Mads Daugaard, president and chief scientific officer of Rakovina Therapeutics. "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." "The reception to our data at SNO has been very encouraging," added Jeffrey Bacha, executive chairman of Rakovina Therapeutics. "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." About Rakovina Therapeutics Inc. Rakovina Therapeutics is a biopharmaceutical research company focused on the development of innovative cancer treatments. The company's work is based on unique technologies for targeting the DNA-damage response powered by artificial intelligence (AI) using the proprietary Deep-Docking and Enki platforms. By using AI, Rakovina can review and optimize drug candidates at a much greater pace than ever before. The company has established a pipeline of distinctive DNA-damage response inhibitors with the goal of advancing one or more drug candidates into human clinical trials in collaboration with pharmaceutical partners. We seek Safe Harbor.