CS231295, a novel AURKB-biased multi-kinase inhibitor, demonstrates synthetic lethality in RB1-deficient tumors and potent intracranial efficacy

Background: The clinical development of multi-kinase inhibitors targeting Aurora kinase B (AURKB) is often limited by dose-limiting toxicities from concurrent VEGFR inhibition, preventing optimal AURKB target suppression. CS231295 was designed as an AURKB-biased inhibitor to overcome this challenge. Methods: Kinase profiling was performed using biochemical and cellular assays. RB1 biomarker validation employed an isogenic NCI-H1048-tet-on-RB1 model. In vivo efficacy and pharmacokinetics were assessed in RB1-deficient SCLC cell-derived and patient-derived xenograft models. Brain penetration and intracranial efficacy were evaluated in orthotopic brain tumor models. Results: CS231295 potently inhibits AURKB (IC₅₀ = 1.32 nM) with a balanced multi-kinase profile. Crucially, its direct antitumor activity-evidenced by caspase-3/9 cleavage at 0.3-3 μM-occurs at concentrations overlapping with or below those needed for anti-angiogenic effects (HUVEC tube inhibition at 3-6 μM), indicating a potential synergistic therapeutic window. CS231295 also demonstrated a synthetic lethal relationship with RB1 deficiency, exhibiting heightened cytotoxicity in RB1-deficient compared to RB1-wildtype small cell lung cancer (SCLC) cells. RB1 overexpression in NCI-H1048 cells increased the IC₅₀ from 0.671 μM to 8.389 μM, confirming RB1 deficiency as a key sensitivity marker. Oral administration induced significant tumor regression in RB1-deficient SCLC models. Prominent brain penetration (brain-to-plasma ratio ≈1) correlated with robust efficacy in an intracranial tumor model. Conclusion: CS231295 achieves effective AURKB inhibition at doses concurrently modulating angiogenesis, overcoming a key limitation of prior agents. Its synthetic lethality with RB1 deficiency and marked intracranial efficacy support its therapeutic potential for RB1-deficient malignancies and brain-involved tumors. IND approvals have been obtained in China and the U.S., facilitating global clinical development.