title: Discovery of Novel Allosteric Eg5 Inhibitors Through Structure-Based Virtual Screening.
abstract: Mitotic kinesin Eg5 is an attractive anticancer drug target. Discovery of Eg5 inhibitors has been focused on targeting the 'monastrol-binding site'. However, acquired drug resistance has been reported for such inhibitors. Therefore, identifying new Eg5 inhibitors which function through a different mechanism(s) could complement current drug candidates and improve drug efficacy. In this study, we explored a novel allosteric site of Eg5 and identified new Eg5 inhibitors through structure-based virtual screening. Experiments with the saturation-transfer difference NMR demonstrated that the identified Eg5 inhibitor SRI35566 binds directly to Eg5 without involving microtubules. Moreover, SRI35566 and its two analogs significantly induced monopolar spindle formation in colorectal cancer HCT116 cells and suppressed cancer cell viability and colony formation. Together, our findings reveal a new allosteric regulation mechanism of Eg5 and a novel drug targeting site for cancer therapy.
authors: Drug Discovery Division, Southern Research Institute, 2000 9th Avenue South, Birmingham, AL, USA.
authors: Wei
authors: W
authors: Zhang
authors: Drug Discovery Division, Southern Research Institute, 2000 9th Avenue South, Birmingham, AL, USA.
authors: Ling
authors: L
authors: Zhai
authors: Drug Discovery Division, Southern Research Institute, 2000 9th Avenue South, Birmingham, AL, USA.
authors: Wenyan
authors: W
authors: Lu
authors: Drug Discovery Division, Southern Research Institute, 2000 9th Avenue South, Birmingham, AL, USA.
authors: Rebecca J
authors: RJ
authors: Boohaker
authors: Drug Discovery Division, Southern Research Institute, 2000 9th Avenue South, Birmingham, AL, USA.
authors: Indira
authors: I
authors: Padmalayam
authors: Drug Discovery Division, Southern Research Institute, 2000 9th Avenue South, Birmingham, AL, USA.
authors: Yonghe
authors: Y
authors: Li
mesh_terms: D000494:Allosteric Regulation; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000473:pathology; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors*; D018613:Microscopy, Confocal; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular
chemical_list: C470243:KIF11 protein, human; D016547:Kinesins
keywords: drug discovery; enzymatic mechanism; structure-based drug design; virtual screening