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

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.
Michael J Ciesielski 1,  Yahao Bu 2,  Stephan A Munich 1,  Paola Teegarden 2,  Michael P Smolinski 2,  James L Clements 2,  Johnson Y N Lau 2,  David G Hangauer 2,  Robert A Fenstermaker 3
Affiliations

Affiliations

  • 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.
PMID: 30238350 DOI: 10.1007/s11060-018-2992-4
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.

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