Our sphingosine kinase inhibitor (SKI) optimization studies originated with the optimization of the SKI-I chemotype by replacement of the substituted benzyl rings with substituted phenyl rings giving rise to the discovery of SKI-178. We have recently reported that SKI-178 is a dual-targeted inhibitor of both sphingosine kinase isoforms (SphK1/2) and a microtubule disrupting agent (MDA). In mechanism-of-action studies, we have shown that these two separate actions synergize to induce cancer cell death in acute myeloid leukemia (AML) cell and animal models. Owning to the effectiveness of SKI-178, we sought to further refine the chemotype while maintaining “on-target” SKI and MDA activities. Herein, we modified the “linker region” between the substituted phenyl rings of SKI-178 through a structure guided approach. These studies have yielded the discovery of an SKI-178 congener, SKI-349, with log-fold enhancements in both SphK inhibition and cytotoxic potency. Importantly, SKI-349 also demonstrates log-fold improvements in therapeutic efficacy in a retro-viral transduction model of MLL-AF9 AML as compared to previous studies with SKI-178. Together, our results strengthen the hypothesis that simultaneous targeting of the sphingosine kinases (SphK1/2) and the induction of mitotic spindle assembly checkpoint arrest, via microtubule disruption, might be an effective therapeutic strategy for hematological malignancies including AML.

我们的鞘氨醇激酶抑制剂 (SKI) 优化研究起源于通过用取代苯环取代取代苯环来优化 SKI-I 化学型，从而发现了 SKI-178。我们最近报道了 SKI-178 是鞘氨醇激酶同种型 (SphK1/2) 和微管破坏剂 (MDA) 的双重靶向抑制剂。在作用机制研究中，我们已经表明，这两种独立的作用协同诱导急性髓性白血病 (AML) 细胞和动物模型中的癌细胞死亡。由于 SKI-178 的有效性，我们试图在保持“目标”SKI 和 MDA 活性的同时进一步完善化学型。在此，我们通过结构引导方法修改了 SKI-178 取代苯环之间的“连接区”。这些研究发现了 SKI-178 同源物 SKI-349，其 SphK 抑制和细胞毒性效力均呈对数倍增强。重要的是，SKI-349 还显示出治疗效果的对数倍改善。复古相比，与SKI-178之前的研究MLL-AF9 AML的-viral传导模型。总之，我们的结果加强了这样的假设，即通过微管破坏同时靶向鞘氨醇激酶 (SphK1/2) 和诱导有丝分裂纺锤体组装检查点停滞可能是治疗血液系统恶性肿瘤（包括 AML）的有效策略。