2. Academic Validation
  3. Discovery and optimization of ATX inhibitors via modeling, synthesis and biological evaluation

Discovery and optimization of ATX inhibitors via modeling, synthesis and biological evaluation

  • Eur J Med Chem. 2018 Mar 25;148:397-409. doi: 10.1016/j.ejmech.2018.02.049.
Anand Balupuri 1,  Myeong Hwi Lee 1,  Sangeun Chae 2,  Eunmi Jung 2,  Woosub Yoon 2,  Yunki Kim 2,  So Jung Son 2,  Jeonghee Ryu 2,  Dae-Hyuck Kang 2,  Young-Jae Yang 2,  Ji-Na You 2,  Hyunjin Kwon 2,  Jong-Woo Jeong 1,  Tae-Sung Koo 1,  Dae-Yon Lee 3,  Nam Sook Kang 4
Affiliations

Affiliations

  • 1 Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, 305-764, Republic of Korea.
  • 2 LegoChem Biosciences, Inc., 8-26 Munoyeongseo-ro, Daedeok-gu, Daejeon, 34302, Republic of Korea.
  • 3 LegoChem Biosciences, Inc., 8-26 Munoyeongseo-ro, Daedeok-gu, Daejeon, 34302, Republic of Korea. Electronic address: dlee@legochembio.com.
  • 4 Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, 305-764, Republic of Korea. Electronic address: nskang@cnu.ac.kr.
PMID: 29477073 DOI: 10.1016/j.ejmech.2018.02.049
Abstract

Autotaxin (ATX) is a potential target for the treatment of various cancers. A new series of ATX inhibitors was rationally designed and synthesized based on our previous study. Biological evaluation and structure-activity relationship (SAR) of this series are discussed. Among fourteen synthesized derivatives, six compounds (2, 3, 4, 12, 13 and 14) exhibited enhanced ATX inhibitory activities with IC50 values in the low nanomolar range. Molecular interactions of all the synthesized compounds within the active site of ATX were studied through molecular docking studies. Herein, we describe our lead optimization efforts that resulted in the identification of a potent ATX inhibitor (compound 4 with IC50 = 1.23 nM, FS-3 and 2.18 nM, bis-pNPP). Furthermore, pharmacokinetic properties of this most promising compound are profiled.

Keywords

ATX inhibitors; Autotaxin; Cancer; Molecular docking; Pharmacokinetics.

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