Discovery of novel serine palmitoyltransferase inhibitors as cancer therapeutic agents.

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 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.

• Authors: Takuto Kojima, Yasutomi Asano, Osamu Kurasawa, Yasuhiro Hirata, Naoki Iwamura, Tzu-Tshin Wong, Bunnai Saito, Yuta Tanaka, Ryosuke Arai, Kazuko Yonemori, Yasufumi Miyamoto, Yoji Sagiya, Masahiro Yaguchi, Sachio Shibata, Akio Mizutani, Osamu Sano, Ryutaro Adachi, Yoshinori Satomi, Megumi Hirayama, Kazunobu Aoyama, Yuto Hiura, Atsushi Kiba, Shuji Kitamura, Shinichi Imamura
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 26 Issue 9 Pg. 2452-2465 (05 15 2018) ISSN: 1464-3391 [Electronic] England
• PMID: 29669694 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Piperidines
• Pyrazoles
• Serine C-Palmitoyltransferase
• ssSPTa

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacokinetics, pharmacology)
• Cell Line, Tumor
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacokinetics, pharmacology)
• High-Throughput Screening Assays
• Humans
• Mice
• Piperidines (chemical synthesis, chemistry, pharmacokinetics, pharmacology)
• Pyrazoles (chemical synthesis, chemistry, pharmacokinetics, pharmacology)
• Serine C-Palmitoyltransferase (antagonists & inhibitors)
• Stereoisomerism
• Structure-Activity Relationship
• Xenograft Model Antitumor Assays