HS-438, a new inhibitor of imatinib-resistant BCR-ABL T315I mutation in chronic myeloid leukemia

Sun-Mi Yun; Kyung Hee Jung; Soo Jung Kim; Zhenghuan Fang; Mi Kwon Son; Hong Hua Yan; Hyunseung Lee; JinHee Kim; Sanghye Shin; Sungwoo Hong; Soon-Sun Hong

doi:10.1016/j.canlet.2014.03.012

HS-438, a new inhibitor of imatinib-resistant BCR-ABL T315I mutation in chronic myeloid leukemia

Cancer Lett. 2014 Jun 28;348(1-2):50-60. doi: 10.1016/j.canlet.2014.03.012. Epub 2014 Mar 18.

Authors

Affiliations

¹ College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea.
² 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.
³ Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
⁴ Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea. Electronic address: [email protected].
⁵ College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea. Electronic address: [email protected].

PMID: 24657654
DOI: 10.1016/j.canlet.2014.03.012

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.

Keywords: BCR-ABL; Chronic myeloid leukemia; HS-438; T315I.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Benzamides / pharmacology*
Benzothiazoles / metabolism
Benzothiazoles / pharmacology*
Binding Sites
Cell Cycle Checkpoints / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm* / genetics
Fusion Proteins, bcr-abl / antagonists & inhibitors*
Fusion Proteins, bcr-abl / genetics*
Fusion Proteins, bcr-abl / metabolism
Imatinib Mesylate
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
Male
Membrane Potential, Mitochondrial / drug effects
Mice
Mice, Nude
Models, Molecular
Mutation*
Piperazines / pharmacology*
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / pharmacology*
Time Factors
Tumor Burden / drug effects
Urea / analogs & derivatives*
Urea / metabolism
Urea / pharmacology

Substances

1-(2-hydroxyethyl)-3-(6-(2-methoxyphenyl)benzo(d)thiazol-2-yl)urea
Antineoplastic Agents
Benzamides
Benzothiazoles
Piperazines
Protein Kinase Inhibitors
Pyrimidines
Imatinib Mesylate
Urea
Fusion Proteins, bcr-abl