Discovery of novel serine palmitoyltransferase inhibitors as cancer therapeutic agents

  • Bioorg Med Chem. 2018 May 15;26(9):2452-2465. doi: 10.1016/j.bmc.2018.04.008.
Takuto Kojima  1 ,  Yasutomi Asano  2 ,  Osamu Kurasawa  2 ,  Yasuhiro Hirata  2 ,  Naoki Iwamura  2 ,  Tzu-Tshin Wong  2 ,  Bunnai Saito  2 ,  Yuta Tanaka  2 ,  Ryosuke Arai  2 ,  Kazuko Yonemori  2 ,  Yasufumi Miyamoto  2 ,  Yoji Sagiya  2 ,  Masahiro Yaguchi  2 ,  Sachio Shibata  2 ,  Akio Mizutani  2 ,  Osamu Sano  2 ,  Ryutaro Adachi  2 ,  Yoshinori Satomi  2 ,  Megumi Hirayama  2 ,  Kazunobu Aoyama  2 ,  Yuto Hiura  2 ,  Atsushi Kiba  2 ,  Shuji Kitamura  2 ,  Shinichi Imamura  3
Affiliations
  • 1. Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-0012, Japan. Electronic address: [email protected].
  • 2. Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-0012, Japan.
  • 3. Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-0012, Japan. Electronic address: [email protected].
PMID: 29669694 DOI: 10.1016/j.bmc.2018.04.008
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.

Keywords
3-KDS; Antitumor efficacy; SPT.
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