KX2-361: a novel orally bioavailable small molecule dual Src/tubulin inhibitor that provides long term survival in a murine model of glioblastoma

J Neurooncol. 2018 Dec;140(3):519-527. doi: 10.1007/s11060-018-2992-4. Epub 2018 Sep 20.

Abstract

Purpose: A major challenge to developing new therapies for patients with malignant brain tumors is that relatively few small molecule anticancer drugs penetrate the blood-brain barrier (BBB) well enough to provide therapeutically effective concentrations in brain tissue before drug exposure in non-CNS tissues results in unacceptable toxicity.

Methods: KX2-361, a member of a novel family of compounds with Src-kinase and tubulin polymerization inhibitory activity, demonstrates good oral bioavailability and readily crosses the BBB in mice. The objective of this study was to investigate the activity of KX2-361 against human and murine glioma cells and assess its therapeutic effect in a syngeneic orthotopic model of glioblastoma.

Results: In addition to reducing the level of Src autophosphorylation in the GL261 murine glioblastoma cell line, KX2-361 binds directly to tubulin and disrupts microtubule architecture in glioma cells maintained in culture.

Conclusions: The drug is active in vivo against orthotopic GL261 gliomas in syngeneic C57BL/6 mice. Long term survival is not observed in mice lacking an adaptive immune system, indicating that KX2-361 works in concert with the host immune system to control tumor growth and promote long-term survival in the GL261 glioma model.

Keywords: Blood–brain barrier; Glioblastoma; KX2-361; Src; Temozolomide; Tubulin.

MeSH terms

  • Acetamides / administration & dosage*
  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Apoptosis
  • Blood-Brain Barrier / metabolism
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / metabolism*
  • Cell Cycle Checkpoints
  • Cell Line, Tumor
  • Disease Models, Animal
  • Glioblastoma / drug therapy
  • Glioblastoma / metabolism*
  • Humans
  • Mice, Inbred C57BL
  • Morpholines / administration & dosage*
  • Phosphorylation
  • Protein Kinase Inhibitors / administration & dosage
  • Pyridines / administration & dosage*
  • Tubulin Modulators / administration & dosage*
  • src-Family Kinases / antagonists & inhibitors*

Substances

  • Acetamides
  • Antineoplastic Agents
  • KX2-361
  • Morpholines
  • Protein Kinase Inhibitors
  • Pyridines
  • Tubulin Modulators
  • src-Family Kinases