title: HS-543 induces apoptosis of Imatinib-resistant chronic myelogenous leukemia with T315I mutation.
abstract: Chronic myeloid leukemia (CML) is characterized by a constitutive activation of Bcr-Abl tyrosine kinase. Bcr-Abl/T315I is the predominant mutation that causes resistance to Imatinib. In the present study, we synthesized a novel Bcr-Abl inhibitor, HS-543, and investigated its effect on cell survival or apoptosis in CML cells bearing Bcr-Abl/T315I (BaF3/T315I) or wild-type Bcr-Abl (BaF3/WT). HS-543 showed anti-proliferative effects in the BaF3/WT cells as well as the BaF3/T315I cells with resistance to Imatinib and strongly inhibited the Bcr-Abl signaling pathway in a dose-dependent manner. Furthermore, it significantly increased the sub G1 phase associated with early apoptosis, with increased levels of cleaved PARP and cleaved caspase-3, as well as the TUNEL-positive apoptotic cells. In addition, we found that HS-543 induced apoptosis with the loss of mitochondrial membrane potential by decreasing the expression of Mcl-1 and survivin, together with increasing that of Bax. In BaF3/T315I xenograft models, HS-543 significantly delayed tumor growth, unlike Imatinib. Our results demonstrate that HS-543 exhibits the induction of apoptosis and anti-proliferative effect by blocking the Bcr-Abl signaling pathway in the T315I-mutated Bcr-Abl cells with resistance to Imatinib. We suggest that HS-543 may be a novel promising agent to target Bcr-Abl and overcome Imatinib resistance in CML patients.
authors.affiliation: College of Medicine, Inha University, Sinheung-dong, Jung-gu, Incheon, Republic of Korea.
authors.forename: Soo Jung
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: College of Medicine, Inha University, Sinheung-dong, Jung-gu, Incheon, Republic of Korea.
authors.forename: Kyung Hee
authors.initials: KH
authors.lastname: Jung
authors.affiliation: College of Medicine, Inha University, Sinheung-dong, Jung-gu, Incheon, Republic of Korea.
authors.forename: Hong Hua
authors.initials: HH
authors.lastname: Yan
authors.affiliation: College of Medicine, Inha University, Sinheung-dong, Jung-gu, Incheon, Republic of Korea.
authors.forename: Mi Kwon
authors.initials: MK
authors.lastname: Son
authors.affiliation: College of Medicine, Inha University, Sinheung-dong, Jung-gu, Incheon, Republic of Korea.
authors.forename: Zhenghuan
authors.initials: Z
authors.lastname: Fang
authors.affiliation: College of Medicine, Inha University, Sinheung-dong, Jung-gu, Incheon, Republic of Korea.
authors.forename: Ye-Lim
authors.initials: YL
authors.lastname: Ryu
authors.affiliation: College of Medicine, Inha University, Sinheung-dong, Jung-gu, Incheon, Republic of Korea.
authors.forename: Hyunseung
authors.initials: H
authors.lastname: Lee
authors.affiliation: College of Medicine, Inha University, Sinheung-dong, Jung-gu, Incheon, Republic of Korea.
authors.forename: Joo Han
authors.initials: JH
authors.lastname: Lim
authors.affiliation: National Research Center for Sexual Medicine, College of Medicine, Inha University, Sinheung-dong, Jung-gu, Incheon, Republic of Korea.
authors.forename: Jun-Kyu
authors.initials: JK
authors.lastname: Suh
authors.affiliation: Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Republic of Korea.|Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
authors.forename: JinHee
authors.initials: J
authors.lastname: Kim
authors.affiliation: Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Republic of Korea.|Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
authors.forename: Soyoung
authors.initials: S
authors.lastname: Lee
authors.affiliation: Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Republic of Korea.|Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
authors.forename: Sungwoo
authors.initials: S
authors.lastname: Hong
authors.affiliation: College of Medicine, Inha University, Sinheung-dong, Jung-gu, Incheon, Republic of Korea.
authors.forename: Soon-Sun
authors.initials: SS
authors.lastname: Hong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology*; D011897:Random Allocation; D015398:Signal Transduction; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C581634:BCR-ABL1 fusion protein, human; D010879:Piperazines; D000068877:Imatinib Mesylate; D014508:Urea; D016044:Fusion Proteins, bcr-abl