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Exp Hematol. 2017 Sep;53:31-42. doi: 10.1016/j.exphem.2017.06.003. Epub 2017 Jun 22.

A novel dual inhibitor of microtubule and Bruton's tyrosine kinase inhibits survival of multiple myeloma and osteoclastogenesis.

Author information

1
Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, USA. Electronic address: pandey@rowan.edu.
2
Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA. Electronic address: kxg21@psu.edu.
3
Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA.
4
Department of Neural and Behavioral Sciences, Pennsylvania State University College of Medicine, Hershey, PA, USA.
5
Division of Hematology and Medical Oncology, M.D. Anderson Cancer Center at Cooper, Camden, NJ, USA.
6
Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA, USA.
7
Division of Pediatric Hematology and Oncology, Pennsylvania State University College of Medicine, Hershey, PA, USA.

Abstract

Bruton's tyrosine kinase (BTK) regulates many vital signaling pathways and plays a critical role in cell proliferation, survival, migration, and resistance. Previously, we reported that a small molecule, KS99, is an inhibitor of tubulin polymerization. In the present study, we explored whether KS99 is a dual inhibitor of BTK and tubulin polymerization. Although it is known that BTK is required for clonogenic growth and resistance, and microtubules are essential for cancer cell growth, dual targeting of these two components has not been explored previously. Through docking studies, we predicted that KS99 interacts directly with the catalytic domain of BTK and inhibits phosphorylation at the Y223 residue and kinase activities. Treatment of KS99 reduces the cell viability of multiple myeloma (MM) and CD138+ cells, with an IC50 of between 0.5 and 1.0 μmol/L. We found that KS99 is able to induce apoptosis in MM cells in a caspase-dependent manner. KS99 suppressed the receptor activator of NF-κB ligand (RANKL)-induced differentiation of macrophages to osteoclasts in a dose-dependent manner and, importantly, inhibited the expression of cytokines associated with bone loss. Finally, we found that KS99 inhibits the in vivo tumor growth of MM cells through the inhibition of BTK and tubulin. Overall, our results show that dual inhibition of BTK and tubulin polymerization by KS99 is a viable option in MM treatment, particularly in the inhibition of refraction and relapse.

PMID:
28647392
DOI:
10.1016/j.exphem.2017.06.003
[Indexed for MEDLINE]

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