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

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

Author information

1
Department of Neurosurgery, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA.
2
Athenex, Inc., 1001 Main Street Suite 600, Buffalo, NY, 14203, USA.
3
Department of Neurosurgery, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA. Robert.Fenstermaker@RoswellPark.org.

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

PMID:
30238350
DOI:
10.1007/s11060-018-2992-4
[Indexed for MEDLINE]

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