Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-0012, Japan.
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-0012, Japan.
Bioorg Med Chem. 2018 May 15;26(9):2452-2465. doi: 10.1016/j.bmc.2018.04.008. Epub 2018 Apr 4.
We pursued serine palmitoyltransferase (SPT) inhibitors as novel cancer therapeutic agents based on a correlation between SPT inhibition and growth suppression of cancer cells. High-throughput screening and medicinal chemistry efforts led to the identification of structurally diverse SPT inhibitors 4 and 5. Both compounds potently inhibited SPT enzyme and decreased intracellular ceramide content. In addition, they suppressed cell growth of human lung adenocarcinoma HCC4006 and acute promyelocytic leukemia PL-21, and displayed good pharmacokinetic profiles. Reduction of 3-ketodihydrosphingosine, the direct downstream product of SPT, was confirmed under in vivo settings after oral administration of compounds 4 and 5. Their anti-tumor efficacy was observed in a PL-21 xenograft mouse model. These results suggested that SPT inhibitors might have potential to be effective cancer therapeutics.
我们基于 SPT 抑制与癌细胞生长抑制之间的相关性，将丝氨酸棕榈酰转移酶（SPT）抑制剂作为新型癌症治疗剂进行研究。高通量筛选和药物化学研究努力导致了结构多样的 SPT 抑制剂 4 和 5 的鉴定。这两种化合物均能强烈抑制 SPT 酶并降低细胞内神经酰胺含量。此外，它们还抑制了人肺腺癌细胞 HCC4006 和急性早幼粒细胞白血病 PL-21 的细胞生长，并表现出良好的药代动力学特征。在口服给予化合物 4 和 5 后，在体内环境下确认了 SPT 的直接下游产物 3-酮二氢鞘氨醇的减少。在 PL-21 异种移植小鼠模型中观察到了它们的抗肿瘤功效。这些结果表明 SPT 抑制剂可能具有成为有效癌症治疗剂的潜力。
