title: HS-438, a new inhibitor of imatinib-resistant BCR-ABL T315I mutation in chronic myeloid leukemia.
abstract: Imatinib is a selective breakpoint cluster region-Abelson (BCR-ABL) tyrosine kinase inhibitor (TKI) that has significantly improved the prognosis of patients with chronic myeloid leukemia (CML). However, T315I gene mutations of the BCR-ABL kinase domain have been shown to confer resistance to imatinib. In the present study, we synthesized a novel BCR-ABL inhibitor, HS-438, and identified its anti-leukemic effects in vitro and in vivo. We found that HS-438 strongly inhibited the expression of BCR-ABL signaling pathways in wild-type BCR-ABL (BaF3/WT) cells as well as T315I-mutated BCR-ABL (BaF3/T315I) cells with resistance to imatinib. HS-438 induced cell cycle arrest, particularly during the G0/G1 cell cycle phase, and induced apoptosis. In BaF3/T315I xenograft models, HS-438 significantly delayed tumor growth, unlike imatinib. In summary, we suggest that HS-438 may be a novel drug candidate with the therapeutic potential to target BCR-ABL and overcome imatinib resistance in patients with CML.
authors.affiliation: College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea.
authors.forename: Sun-Mi
authors.initials: SM
authors.lastname: Yun
authors.affiliation: College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea; College of Pharmacy, Chonnam National University, Gwang-Ju 300, Republic of Korea.
authors.forename: Kyung Hee
authors.initials: KH
authors.lastname: Jung
authors.affiliation: College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea.
authors.forename: Soo Jung
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea.
authors.forename: Zhenghuan
authors.initials: Z
authors.lastname: Fang
authors.affiliation: College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea.
authors.forename: Mi Kwon
authors.initials: MK
authors.lastname: Son
authors.affiliation: College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea.
authors.forename: Hong Hua
authors.initials: HH
authors.lastname: Yan
authors.affiliation: College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea.
authors.forename: Hyunseung
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
authors.forename: JinHee
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
authors.forename: Sanghye
authors.initials: S
authors.lastname: Shin
authors.affiliation: Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea. Electronic address: hongorg@kaist.ac.kr.
authors.forename: Sungwoo
authors.initials: S
authors.lastname: Hong
authors.affiliation: College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea. Electronic address: hongs@inha.ac.kr.
authors.forename: Soon-Sun
authors.initials: SS
authors.lastname: Hong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D052160:Benzothiazoles / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D014508:Urea / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
chemical_list: C000589392:1-(2-hydroxyethyl)-3-(6-(2-methoxyphenyl)benzo(d)thiazol-2-yl)urea; D000970:Antineoplastic Agents; D001549:Benzamides; D052160:Benzothiazoles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D014508:Urea; D016044:Fusion Proteins, bcr-abl
keywords: BCR-ABL; Chronic myeloid leukemia; HS-438; T315I