Preclinical Compounds Perform Better Than Existing Drugs
Research Report

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Disclosures for Leede Financial Inc., Rakovina Therapeutics, November 7, 2025

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Rakovina Therapeutics Inc. (RKV:TSX.V) and partner Variational AI presented preclinical data on their novel artificial intelligence-designed ATR inhibitors from their kt-5000AI program at the International Conference on Molecular Targets and Cancer Therapeutics in October, reported Dr. Douglas Loe, managing director and analyst at Leede Financial Inc., in a November 7 Week in Review research note. Rakovina uses AI to discover and develop new cancer therapies.

"Preclinical data showed that all three [Rakovina] compounds needed significantly lower drug concentrations to block ATR activity versus existing, clinical-stage drugs from competitors AstraZeneca Plc (AZN:NYSE; AZN:LON), Merck KGaA (MKGAY:OTCPK) and Bayer AG (BAYRY:OTCMKTS; BAYN:XETRA)," Loe wrote.

Loe explained that ATR, or ataxia telangiectasia and Rad3-related protein, is a cancer target central to the DNA Damage Response (DDR) pathway. Cancer cells use the ATR pathway to survive high levels of DNA damage and replication stress. By blocking this DDR enzyme, the inhibitors cause genomic instability and cell death, or synthetic lethality.

What the Data Showed

Rakovina and Variational AI's three lead kd-5000AI compounds are referred to as Compound A, Compound B, and Compound C. Preclinical data showed that all three compounds needed much lower drug concentrations to block ATR activity than these existing, clinical-stage drugs did: AstraZeneca's ceralasertib, Merck's tuvusertib, and Bayer's elimusertib. Specifically, Compound A achieved 50% enzyme inhibition at just 119 nanomolars (119 nM), Compound B at 167 nM, and Compound C at 175 nM. All three were more potent than the comparator drugs, ceralasertib (420 nM), tuvusertib (4,680 nM), and elimusertib (1,404 nM).

Also, all three Rakovina compounds showed they could successfully inhibit two targets simultaneously, in this case ATR and mTOR kinases. Loe noted that this dual-targeting ability could provide synergistic anti-cancer effects.

The clinical-stage ATR inhibitors now in development have limited central nervous system penetration and thus are suboptimal for the treatment of brain tumors and brain metastases, according to Loe. However, Rakovina's Compound A and Compound B showed they can penetrate the CNS, Compound B more so than A.

After administering a 5 milligram per kilogram (5 mg/kg) dose, drug concentration measurements showed that Compound B achieved 51.4% of its plasma levels in brain tissue. This means the drug effectively crossed the blood-brain barrier and accumulated in the brain at a therapeutic concentration. Compound A, in comparison, showed more modest brain penetration at 11.2%.

"This is a significant advancement as no other ATR inhibitor in clinical development has demonstrated meaningful brain exposure," Loe wrote. "In vitro cellular efficacy studies are ongoing."

Third-Party Validation

Even though Rakovina's kt-5000AI program is preclinical, it "remains noteworthy in the context of broader AI-enabled drug discovery validation trends," Loe pointed out. Variational AI's Enki platform powers the kt-5000AI program. Variational AI recently landed a partnership with Merck for the Enki platform, worth potentially up to US$349 million (US$349M) in milestone-based payments. This partnership represents significant third-party validation of the underlying AI technology driving Rakovina's discovery work. Also, this is in line with the broader trend of major pharmaceutical companies, such as Eli Lilly & Co. (LLY:NYSE) and Johnson & Johnson (JNJ:NYSE), making infrastructure-level investments in AI-driven drug development to accelerate discovery timelines and lower risk.

Rakovina uses two externally validated AI platforms, one being Variational AI's Enki. The other is Rakovina's proprietary Deep Docking, which produced compounds licensed to Roche Holding AG (RHHBY:OTCQX) for US$140M.