XNW34017的发现与表征：一种首创、口服生物利用度高且可穿透脑部的AURKA-MYC降解剂

Aurora-A is a serine/threonine kinase essential for mitotic progression and is overexpressed in a broad range of solid tumors and hematological malignancies. Inhibiting AURKA's kinase activity can suppress tumor progression. Several AURKA inhibitors have been developed and tested in clinical trials. Although AURKA inhibitors have shown strong preclinical efficacy, their clinical development was not successful. Beyond its catalytic role, AURKA can stabilize MYC family proteins to protect them from proteasomal degradation. Consequently, unlike the AURKA inhibitors, degraders of AURKA can eliminate the entire AURKA protein, simultaneously abolishing its kinase activity and scaffolding function. Compared with inhibitors, this dual mechanism may offer enhanced antitumor efficacy and expanded therapeutic window, making degradation of AURKA and subsequent MYC a more effective therapeutic strategy. Based on this rationale, we developed the first-in-class bifunctional AURKA degraders, which have shown efficient degradation of AURKA and MYC family proteins (c-Myc, L-Myc, and N-Myc) in MYC-driven cell lines. MoA studies with early lead compounds confirmed that AURKA degradation is on-target, E3- and UPS-dependent. qPCR experiment further demonstrated that neither AURKA nor MYC protein level change is associated with transcriptional changes, validating our therapeutic strategy of degrading AURKA to induce MYC degradation. After extensive optimization, XNW34017 was selected as the development candidate. XNW34017 exhibits favorable PK properties, including >50% oral bioavailability across species (mouse, rat, and dog), and evidence of brain penetration. The compound selectively and potently degrades AURKA, leading to subsequent degradation of MYC family proteins. In the NCI-H209 SCLC model with L-MYC overexpression, oral QD dosing of XNW34017 induced rapid AURKA degradation at day 1 and efficient L-MYC degradation at day 3, which then led to complete tumor regression. PD studies revealed a strong correlation between L-MYC degradation and enhanced tumor response. In tumor models with c-MYC and N-MYC overexpression, XNW34017 also demonstrated superior tumor growth inhibition (TGI) while AURKA inhibitor showed limited efficacy. Notably, in the NCI-H1975 NSCLC brain metastasis model with c-MYC overexpression, oral QD dosing of XNW34017 achieved 98% TGI at day 21, demonstrating its efficacy against MYC-driven CNS disease. DRF and GLP toxicity studies of XNW34017 in rats and dogs demonstrated good tolerability with a reasonable safety margin, suggesting that the clinical risks are manageable. Observed toxicities were consistent with on-target degradation of AURKA, with no unexpected safety risk observed. Together, our MOA and preclinical studies support the advancement of XNW34017 into clinical development for MYC-driven malignancies.