Dual TTK/CLK2 inhibitor, CC-671, selectively antagonizes ABCG2-mediated multidrug resistance in lung cancer cells.

ABSTRACT: One pivotal factor that leads to multidrug resistance (MDR) is the overexpression of ABCG2. Therefore, tremendous effort has been devoted to the search of effective reversal agents to overcome ABCG2-mediated MDR. CC-671 is a potent and selective inhibitor of both TTK (human protein kinase monopolar spindle 1 [hMps1]) and CDC like kinase 2 (CLK2). It represents a new class of cancer therapeutic drugs. In this study, we show that CC-671 is an effective ABCG2 reversal agent that enhances the efficacy of chemotherapeutic drugs in ABCG2-overexpressing lung cancer cells. Mechanistic studies show that the reversal effect of CC-671 is primarily attributed to the inhibition of the drug efflux activity of ABCG2, which leads to an increased intracellular level of chemotherapeutic drugs. In addition, CC-671 does not alter the protein expression or subcellular localization of ABCG2. The computational molecule docking analysis suggests CC-671 has high binding affinity to the drug-binding site of ABCG2. In conclusion, we reveal the interaction between CC-671 and ABCG2, providing a rationale for the potential combined use of CC-671 with ABCG2 substrate to overcome MDR.

SUBMITTER: Wu ZX 

PROVIDER: S-EPMC7419038 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature