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

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.

• Authors: Michael J Ciesielski, Yahao Bu, Stephan A Munich, Paola Teegarden, Michael P Smolinski, James L Clements, Johnson Y N Lau, David G Hangauer, Robert A Fenstermaker
• Journal: Journal of neuro-oncology (J Neurooncol) Vol. 140 Issue 3 Pg. 519-527 (Dec 2018) ISSN: 1573-7373 [Electronic] United States
• PMID: 30238350 (Publication Type: Journal Article)

Chemical References

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

Topics

• Acetamides (administration & dosage)
• Animals
• Antineoplastic Agents (administration & dosage)
• Apoptosis
• Blood-Brain Barrier (metabolism)
• Brain Neoplasms (drug therapy, metabolism)
• Cell Cycle Checkpoints
• Cell Line, Tumor
• Disease Models, Animal
• Glioblastoma (drug therapy, 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)