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Insights from Pim1 structure for anti-cancer drug design

Naoko Ogawa1, Hitomi Yuki, Akiko Tanaka

  • 1RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan.

Expert Opinion on Drug Discovery
|September 26, 2012
PubMed
Abstract

Insights

Developing potent Pim1 inhibitors is crucial for cancer therapy. Targeting both ATP and substrate binding sites offers a promising strategy for novel drug discovery in hematologic malignancies and prostate cancer.

Area of Science:

  • Biochemistry
  • Medicinal Chemistry
  • Oncology

Background:

  • Pim1 kinase is a constitutively active serine/threonine kinase and a potent oncogene.
  • Overexpressed in hematologic malignancies and solid cancers, Pim1 regulates cell proliferation and survival.
  • Despite numerous inhibitors developed, no Pim1-targeting drug is currently approved.

Purpose of the Study:

  • To review Pim1 inhibitors based on structural analysis of Pim1-inhibitor complexes.
  • To classify and summarize inhibitors by their interactions with Pim1 residues.
  • To guide the design of potent and selective Pim1 inhibitors.

Main Methods:

  • Literature search of PubMed and Protein Data Bank (PDB).
  • Structural analysis of Pim1-inhibitor complexes.
  • Classification of inhibitors based on binding interactions.

Main Results:

  • Over 400 small molecular Pim1 inhibitors (IC(50)/Ki < 10 μM) are documented.
  • Inhibitors interact with specific Pim1 residues within the ATP binding site and substrate binding regions.
  • Structural insights facilitate understanding of inhibitor efficacy.

Conclusions:

  • Simultaneous interaction with ATP binding site (Lys67, Glu121, Phe49) and substrate binding residues (Asp128, Asp131, Glu171) is proposed for potent and selective inhibitors.
  • Development of Pim1 inhibitors may offer new therapeutic strategies.
  • Potential applications include hematological malignancies and prostate cancer.

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