Discovery of novel serine palmitoyltransferase inhibitors as cancer therapeutic agents. Issue 9 (15th May 2018)

• Record Type: Journal Article
• Authors: Kojima, Takuto; Asano, Yasutomi; Kurasawa, Osamu; Hirata, Yasuhiro; Iwamura, Naoki; Wong, Tzu-Tshin; Saito, Bunnai; Tanaka, Yuta; Arai, Ryosuke; Yonemori, Kazuko; Miyamoto, Yasufumi; Sagiya, Yoji; Yaguchi, Masahiro; Shibata, Sachio; Mizutani, Akio; Sano, Osamu; Adachi, Ryutaro; Satomi, Yoshinori; Hirayama, Megumi; Aoyama, Kazunobu; Hiura, Yuto; Kiba, Atsushi; Kitamura, Shuji; Imamura, Shinichi
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 9(2018)
• Page Start: 2452
• Page End: 2465
• Publication Date: 2018-05-15
• Subjects: SPT -- 3-KDS -- Antitumor efficacy; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.04.008
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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 inhibitors4 and5 . 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 compounds4 and5 . 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.