KX2-361: a novel orally bioavailable small molecule dual Src/tubulin inhibitor that provides long term survival in a murine model of glioblastoma
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.
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.
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.
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.
KeywordsGlioblastoma Temozolomide Blood–brain barrier KX2-361 Src Tubulin
The authors are grateful for critical manuscript review and helpful suggestions provided by Drs. Sameer Urgaonkar and Murray Cutler.
MC, SM, and YB designed and conducted the majority of experiments and were primarily responsible for data analysis. MS designed and synthesized KX2-601. MC and JC wrote the majority of the paper. PT conducted the experiments assessing the impact of KX2-361 on Src autophosphorylation. JL, DH, and RF oversaw all aspects of operations and provided technical and expert advice.
This project was in part supported by the Roswell Park Alliance Foundation and National Cancer Institute Cancer Center Support Grant NIH P30 CA016056.
Compliance with ethical standards
Conflict of interest
YB, PT, MS, JC, JL, and DH hold equity in Athenex, Inc. MC, SM, and RF declare no conflict of interest.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.
Research involving human participants and/or animals
This article does not contain any studies with human participants performed by any of the authors.
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