Puquitinib, a novel orally available PI3Kδ inhibitor, exhibits potent antitumor efficacy against acute myeloid leukemia

Cancer Sci. 2017 Jul;108(7):1476-1484. doi: 10.1111/cas.13263. Epub 2017 May 23.

Abstract

The PI3Kδ isoform (PIK3CD), also known as P110δ, is predominately expressed in leukocytes and has been implicated as a potential target in the treatment of hematological malignancies. In this report, we detailed the pharmacologic properties of puquitinib, a novel, orally available PI3Kδ inhibitor. Puquitinib, which binds to the ATP-binding pocket of PI3Kδ, was highly selective and potent for PI3Kδ relative to other PI3K isoforms and a panel of protein kinases, exhibiting low-nanomolar biochemical and cellular inhibitory potencies. Additional cellular profiling demonstrated that puquitinib inhibited proliferation, induced G1 -phase cell-cycle arrest and apoptosis in acute myeloid leukemia (AML) cell lines, through downregulation of PI3K signaling. In in vivo AML xenografts, puquitinib alone showed stronger efficacy than the well-known p110δ inhibitor, CAL-101, in association with a reduction in AKT and ERK phosphorylation in tumor tissues, without causing noticeable toxicity. Furthermore, the combination of puquitinib with cytotoxic drugs, especially daunorubicin, yielded significantly stronger antitumor efficacy compared with each agent alone. Thus, puquitinib is a promising agent with pharmacologic properties that are favorable for the treatment of AML.

Keywords: Acute myeloid leukemia; CAL-101; PI3K signaling; PI3Kδ; puquitinib.

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / pharmacology
  • Aminoquinolines / pharmacology*
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Blotting, Western
  • Cell Proliferation / drug effects
  • Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
  • Humans
  • Leukemia, Myeloid, Acute*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / pharmacology
  • Signal Transduction / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Aminoquinolines
  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • puquitinib
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CD protein, human
  • Adenine