Clinically relevant GSK‑3β inhibitor 9‑ING‑41 is active as a single agent and in combination with other antitumor therapies in human renal cancer

Int J Mol Med. 2020 Feb;45(2):315-323. doi: 10.3892/ijmm.2019.4427. Epub 2019 Dec 12.

Abstract

Glycogen synthase kinase‑3 (GSK‑3), a serine/threonine kinase, is involved in a broad range of pathological processes including cancer. GSK‑3 has two isoforms, GSK‑3α and GSK‑3β, and GSK‑3β has been recognized as a therapeutic target for the development of new anticancer drugs. The present study aimed to investigate the antitumor effects of 9‑ING‑41, which is a maleimide‑based ATP‑competitive small molecule GSK‑3β inhibitor active in patients with advanced cancer. In renal cancer cell lines, treatment with 9‑ING‑41 alone induced cell cycle arrest and apoptosis, and autophagy inhibitors increased the antitumor effects of 9‑ING‑41 when used in combination. Treatment with 9‑ING‑41 potentiated the antitumor effects of targeted therapeutics and increased the cytotoxic effects of cytokine‑activated immune cells on renal cancer cell lines. These results provided a compelling rationale for the inclusion of patients with renal cancer in studies of 9‑ING‑41, both as a single agent and in combination with current standard therapies.

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Glycogen Synthase Kinase 3 beta / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Humans
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / metabolism
  • Maleimides / chemistry
  • Maleimides / pharmacology*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*

Substances

  • Antineoplastic Agents
  • Maleimides
  • Protein Kinase Inhibitors
  • maleimide
  • Glycogen Synthase Kinase 3 beta