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

• Published in: Journal of neuro-oncology 2018-12, Vol.140 (3), p.519-527
• Main Authors: Ciesielski, Michael J., Bu, Yahao, Munich, Stephan A., Teegarden, Paola, Smolinski, Michael P., Clements, James L., Lau, Johnson Y. N., Hangauer, David G., Fenstermaker, Robert A.
• Format: Article
• Language: English
• Subjects: Acetamides - administration & dosage; Animal models; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic drugs; Antitumor agents; Apoptosis; Bioavailability; Blood-brain barrier; Blood-Brain Barrier - metabolism; Brain cancer; Brain Neoplasms - drug therapy; Brain Neoplasms - metabolism; Brain tumors; Cell culture; Cell Cycle Checkpoints; Cell Line, Tumor; Central nervous system; Disease Models, Animal; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - metabolism; Glioma cells; Humans; Immune system; Immunosuppressive agents; Laboratory Investigation; Medicine; Medicine & Public Health; Mice, Inbred C57BL; Morpholines - administration & dosage; Neurology; Oncology; Phosphorylation; Polymerization; Protein Kinase Inhibitors - administration & dosage; Pyridines - administration & dosage; src-Family Kinases - antagonists & inhibitors; Toxicity; Tubulin; Tubulin Modulators - administration & dosage
• ISSN: 0167-594X; 1573-7373
• DOI: 10.1007/s11060-018-2992-4

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.