Discovery of novel serine palmitoyltransferase inhibitors as cancer therapeutic agents.
Kojima T, Asano Y, Kurasawa O, Hirata Y, Iwamura N, Wong TT, Saito B, Tanaka Y, Arai R, Yonemori K, Miyamoto Y, Sagiya Y, Yaguchi M, Shibata S, Mizutani A, Sano O, Adachi R, Satomi Y, Hirayama M, Aoyama K, Hiura Y, Kiba A, Kitamura S, Imamura S.
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.