Discovery of novel serine palmitoyltransferase inhibitors as cancer therapeutic agents

• Published in: Bioorganic & medicinal chemistry Vol. 26; no. 9; pp. 2452 - 2465
• Main 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
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.05.2018; Elsevier
• Subjects: 3-KDS; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Antitumor efficacy; Biochemistry & Molecular Biology; Cell Line, Tumor; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; High-Throughput Screening Assays; Humans; Life Sciences & Biomedicine; Mice; Pharmacology & Pharmacy; Physical Sciences; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - pharmacokinetics; Piperidines - pharmacology; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacokinetics; Pyrazoles - pharmacology; Science & Technology; Serine C-Palmitoyltransferase - antagonists & inhibitors; SPT; Stereoisomerism; Structure-Activity Relationship; Xenograft Model Antitumor Assays; 3-KDS; Antitumor efficacy; SPT; SPHINGOLIPID METABOLISM; PALMITOYL TRANSFERASE; TARGETS; DERIVATIVES
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2018.04.008

[Display omitted] 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.