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

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.

• Authors: Manoj K Pandey, Krishne Gowda, Shen-Shu Sung, Thomas Abraham, Tulin Budak-Alpdogan, Giampolo Talamo, Sinisa Dovat, Shantu Amin
• Journal: Experimental hematology (Exp Hematol) Vol. 53 Pg. 31-42 (09 2017) ISSN: 1873-2399 [Electronic] Netherlands
• PMID: 28647392 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

Chemical References

• NF-kappa B
• RANK Ligand
• STAT3 Transcription Factor
• Stat3 protein, mouse
• Tubulin Modulators
• Protein-Tyrosine Kinases
• Agammaglobulinaemia Tyrosine Kinase
• Btk protein, mouse
• Jak2 protein, mouse
• Janus Kinase 2

Topics

• Agammaglobulinaemia Tyrosine Kinase
• Animals
• Apoptosis (drug effects)
• Cells, Cultured
• Janus Kinase 2 (metabolism)
• Mice
• Multiple Myeloma (drug therapy, mortality, pathology)
• NF-kappa B (metabolism)
• Osteoclasts (drug effects, physiology)
• Osteogenesis (drug effects)
• Phosphorylation
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• RANK Ligand (pharmacology)
• STAT3 Transcription Factor (metabolism)
• Tubulin Modulators (pharmacology)