Aurora kinase inhibitors such as alisertib can destabilize MYC-family oncoproteins and have demonstrated compelling anti-tumor efficacy. In this study, we report 6K465, a novel pyrimidine-based Aurora A (AURKA) inhibitor that reduces levels of c-MYC and N-MYC oncoproteins more potently than alisertib. In an analysis of the antiproliferative effect of 6K465, the sensitivities of small cell lung cancer (SCLC) and breast cancer (BC) cell lines to 6K465 were strongly associated with the protein levels of c-MYC and/or N-MYC. We also report DBPR728, an acyl-based prodrug of 6K465 bearing fewer hydrogen-bond donors that exhibited 10-fold improved oral bioavailability. DBPR728 induced durable tumor regression of c-MYC- and/or N-MYC- overexpressing xenografts including SCLC, triple-negative breast cancer (TNBC), hepatocellular carcinoma and medulloblastoma using a 5-on-2-off or once-a-week dosing regimen on a 21-day cycle. A single oral dose of DBPR728 at 300 mg/kg induced c-MYC reduction and cell apoptosis in the tumor xenografts for more than 7 days. The inhibitory effect of DBPR728 at a reduced dosing frequency was attributed to its uniquely high tumor/plasma ratio (3.6-fold within 7 days) and the long tumor half-life of active moiety 6K465. Furthermore, DBPR728 was found to synergize with the mTOR inhibitor everolimus to suppress c-MYC- or N-MYC- driven SCLC. Collectively, these results suggest DBPR728 has the potential to treat cancers overexpressing c-MYC- and/or N-MYC.

中文翻译：

---

发现一种长半衰期 AURKA 抑制剂，可作为单一疗法或与依维莫司联合治疗 MYC 扩增实体瘤

极光激酶抑制剂（例如 alisertib）可以破坏 MYC 家族癌蛋白的稳定性，并已证明具有引人注目的抗肿瘤功效。在这项研究中，我们报告了 6K465，这是一种新型的基于嘧啶的 Aurora A (AURKA) 抑制剂，它比 alisertib 更有效地降低 c-MYC 和 N-MYC 癌蛋白水平。在对 6K465 抗增殖作用的分析中，小细胞肺癌 (SCLC) 和乳腺癌 (BC) 细胞系对 6K465 的敏感性与 c-MYC 和/或 N-MYC 的蛋白水平密切相关。我们还报道了 DBPR728，一种基于酰基的 6K465 前药，具有较少的氢键供体，口服生物利用度提高了 10 倍。 DBPR728 使用 5-on-2-off 或每周一次诱导 c-MYC- 和/或 N-MYC- 过表达异种移植物的持久肿瘤消退，包括 SCLC、三阴性乳腺癌 (TNBC)、肝细胞癌和髓母细胞瘤21天为一个周期的给药方案。单次口服 300 mg/kg 剂量的 DBPR728 可诱导肿瘤异种移植物中 c-MYC 减少和细胞凋亡，持续时间超过 7 天。 DBPR728 在降低给药频率时的抑制作用归因于其独特的高肿瘤/血浆比率（7 天内 3.6 倍）和活性部分 6K465 的长肿瘤半衰期。此外，发现 DBPR728 与 mTOR 抑制剂依维莫司协同作用，抑制 c-MYC 或 N-MYC 驱动的 SCLC。总的来说，这些结果表明 DBPR728 具有治疗过度表达 c-MYC-和/或 N-MYC 的癌症的潜力。