This update follows our post describing the Rakovina Therapeutics–Variational AI collaboration. For context, see: Accelerating the discovery of brain-penetrant ATR inhibitors with Enki™
What’s new since May?
Building on the initial hit series Variational AI designed with Enki™, Rakovina Therapeutics presented new data at the AACR–NCI–EORTC 2025 Molecular Targets & Cancer Therapeutics meeting. The poster reports notable progress across potency, selectivity, metabolic stability, and in vivo PK/brain exposure for multiple Enki-generated ATR inhibitor chemotypes.
As a reminder of the workflow to date: Enki™ generated a prioritized list of 138 candidates against a preclinical TPP emphasizing ATR potency, selectivity against related PIKK family members, and CNS penetration; 35 were synthesized and advanced into wet-lab testing, delivering multiple hits with >50% showing ATR inhibition at 1 µM, in less than 12 months. Below is a summary of the new results.
Potency vs. reference ATR inhibitors
Dose–response curves against recombinant ATR show that several Enki-designed compounds are as potent as—or more potent than—reference clinical-stage ATR inhibitors (including ceralasertib, tuvusertib, and elimusertib).
This confirms that Enki’s generative search can reach benchmark-level target potency while exploring novel chemical space. (Poster panel: “Compound Potency”.)
Selectivity across the PIKK family
Selectivity profiles indicate that our compounds match the PIKK-family selectivity of the clinical references, an essential requirement to minimize off-target liabilities typical of this kinase family. Maintaining this selectivity while pushing for CNS exposure is a key program goal, and the latest data indicate no trade-off to date. (Poster panel: “Selectivity vs. PIKK family kinases”.)
Metabolic stability
In human liver microsomes, compounds demonstrated favorable metabolic stability after 45 minutes of incubation, supporting suitability for in vivo studies and giving medicinal chemists a strong foundation for subsequent optimization cycles. (Poster panel: “Metabolic Stability”.)
Mouse pharmacokinetic profiling and CNS exposure
Following single-dose intraperitoneal administration (5 mg/kg) in mice, tested compounds were well tolerated and achieved measurable brain exposure, with varying CNS penetration across the series quantified by LC/MS in plasma and brain. This variability reveals structure–property relationships that we can exploit to systematically increase brain exposure without sacrificing potency or selectivity. (Poster panel: “Mouse Pharmacokinetic Profiling”.)
Why does this matter?
Achieving CNS penetration has limited many first-generation ATR programs, despite the compelling biology as a treatment approach for brain tumors and brain metastases. The new data suggest that CNS-accessible ATR inhibitors are attainable with Enki’s generative, multi-objective design, which jointly optimizes potency, selectivity, and ADME/CNS properties from the outset—rather than discovering potency first and back-filling other developability properties later.
Enki’s advantage stems from constructing a smooth chemical search space that supports efficient, multi-property optimization and rapid iteration with medicinal chemistry. This approach searches far beyond fixed screening libraries and prioritizes chemically valid, synthesizable designs tailored to the program’s TPP—driving both speed (design-to-hit in under a year) and quality (early selectivity, stability, and PK signals).
Conclusion & what’s next
These results illustrate what’s possible when generative AI augments traditional discovery:
- Speed: from TPP to multiple validated hits and into in vivo PK/brain exposure studies in months, not years.
- Quality: hits that already balance ATR potency, PIKK selectivity, and metabolic stability, with emerging CNS exposure that can be further optimized.
Next steps include continued in vitro / in vivo characterization and data-informed lead optimization to further elevate brain exposure while preserving selectivity and safety margins. The poster (embedded below) provides figure-level details and methods.
Interested in collaborating?
If you’re exploring targets where CNS penetration, multi-objective design, or fast hit-to-lead matters, we’d be happy to collaborate. Enki™ integrates smoothly with real-world medicinal chemistry workflows to deliver more—and better—shots on goal.