Aurora kinase inhibitors have attracted a great deal of interest as a new class of antimitotic agents. We report a novel class of Aurora inhibitors based on a pentacyclic scaffold. A prototype pentacyclic inhibitor 32 (AKI-001) derived from two early lead structures improves upon the best properties of each parent and compares favorably to a previously reported Aurora inhibitor, 39 (VX-680). The inhibitor exhibits low nanomolar potency against both Aurora A and Aurora B enzymes, excellent cellular potency (IC50 < 100 nM), and good oral bioavailability. Phenotypic cellular assays show that both Aurora A and Aurora B are inhibited at inhibitor concentrations sufficient to block proliferation. Importantly, the cellular activity translates to potent inhibition of tumor growth in vivo. An oral dose of 5 mg/kg QD is well tolerated and results in near stasis (92% TGI) in an HCT116 mouse xenograft model.

中文翻译：

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具有高体内效力和口服生物利用度的五环极光激酶抑制剂（AKI-001）。

作为一类新型的抗有丝分裂剂，极光激酶抑制剂引起了人们的极大兴趣。我们报告基于五环支架的一类新型的Aurora抑制剂。源自两个早期铅结构的原型五环抑制剂32（AKI-001）改善了每个亲本的最佳性能，并且与先前报道的Aurora抑制剂39（VX-680）相比具有优势。该抑制剂对Aurora A和Aurora B酶均具有较低的纳摩尔浓度，具有出色的细胞效价（IC50 <100 nM），并且口服生物利用度良好。表型细胞分析表明，Aurora A和Aurora B都在足以阻止增殖的抑制剂浓度下被抑制。重要的是，细胞活性转化为体内肿瘤生长的有效抑制。