Design and synthesis of an in vivo-efficacious PIM3 kinase inhibitor as a candidate anti-pancreatic cancer agent

  • Bioorg Med Chem Lett. 2015 Dec 15;25(24):5687-93. doi: 10.1016/j.bmcl.2015.10.098.
Hirofumi Nakano  1 ,  Tsukasa Hasegawa  1 ,  Nae Saito  1 ,  Kaoru Furukawa  2 ,  Naofumi Mukaida  2 ,  Hirotatsu Kojima  1 ,  Takayoshi Okabe  1 ,  Tetsuo Nagano  3
Affiliations
  • 1. Drug Discovery Initiative, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
  • 2. Division of Molecular Bioregulation, Cancer Microenvironment Research Program, Cancer Research Institute, Kanazawa University, 13-1 Kakuma-machi, Kanazawa, Japan.
  • 3. Drug Discovery Initiative, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan. Electronic address: [email protected].
PMID: 26547690 DOI: 10.1016/j.bmcl.2015.10.098
Abstract

Serine/threonine kinase PIM3 is a potential therapeutic target for pancreatic Cancer. Here, we describe the evolution of our previous PIM1 Inhibitor 1 into PIM3 Inhibitor 11 guided by use of the crystal structure of PIM1 as a surrogate to provide a basis for rational modification. Compound 11 potently inhibits PIM3 kinase activity, as well as growth of several pancreatic Cancer cell lines. In a mouse xenograft model, 11 inhibited growth of human pancreatic Cancer cell line PCI66 with negligible body weight loss. Thus, 11 appears to be a promising lead compound for further optimization to develop new anti-pancreatic Cancer agents.

Keywords
Anti-cancer agent; Drug design; Kinase inhibitor; PIM3; Pancreatic cancer.