title: A novel compound against oncogenic Aurora kinase A overcomes imatinib resistance in chronic myeloid leukemia cells.
abstract: Drug resistance still represents a major obstacle to successful chronic myeloid leukemia (CML) treatment and novel compounds or strategies to override this challenging problem are urgently required. Here, we evaluated a novel compound AKI603 against oncogenic Aurora kinase A (Aur-A) in imatinib-resistant CML cells. We found that Aur-A was highly activated in imatinib-resistant KBM5-T315I cells. AKI603 significantly inhibited the phosphorylation of Aur-A kinase at Thr288, while had little inhibitory effect on BCR-ABL kinase in both KBM5 and KBM5-T315I cells. AKI603 inhibited cell viability, and induced cell cycle arrest with polyploidy accumulation in KBM5 and KBM5-T315I cells. Moreover, inhibition of Aur-A kinase by AKI603 suppressed colony formation capacity without promoting obvious apoptosis. Importantly, AKI603 promoted cell differentiation in both CML cell types. Thus, our study suggested the potential clinical use of small molecule Aurora kinase inhibitor AKI603 to overcome imatinib resistance in CML treatment.
authors: Department of Hematology, The Third Affiliated Hospital, Sun Yat-sen University, Sun Yat-sen Institute of Hematology, Guangzhou 510630, P.R. China.
authors: Zi-Jie
authors: ZJ
authors: Long
authors: Department of Hematology, The Third Affiliated Hospital, Sun Yat-sen University, Sun Yat-sen Institute of Hematology, Guangzhou 510630, P.R. China.
authors: Le-Xun
authors: LX
authors: Wang
authors: State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China.
authors: Fei-Meng
authors: FM
authors: Zheng
authors: Department of Hematology, The Third Affiliated Hospital, Sun Yat-sen University, Sun Yat-sen Institute of Hematology, Guangzhou 510630, P.R. China.
authors: Jia-Jie
authors: JJ
authors: Chen
authors: Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P.R. China.
authors: Yu
authors: Y
authors: Luo
authors: Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, P.R. China.
authors: Xi-Xiang
authors: XX
authors: Tu
authors: Department of Hematology, The Third Affiliated Hospital, Sun Yat-sen University, Sun Yat-sen Institute of Hematology, Guangzhou 510630, P.R. China.
authors: Dong-Jun
authors: DJ
authors: Lin
authors: Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P.R. China.
authors: Gui
authors: G
authors: Lu
authors: Department of Hematology, The Third Affiliated Hospital, Sun Yat-sen University, Sun Yat-sen Institute of Hematology, Guangzhou 510630, P.R. China.
authors: Quentin
authors: Q
authors: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011123:Polyploidy; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: C000597114:AKI603; D000970:Antineoplastic Agents; D011720:Pyrazoles; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C576917:AURKA protein, human; D064096:Aurora Kinase A