Discovery of (E)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)propanamide (CHMFL-ABL-121) as a highly potent ABL kinase inhibitor capable of overcoming a variety of ABL mutants including T315I for chronic myeloid leukemia

Liu, Xuesong; Wang, Beilei; Chen, Cheng; Jiang, Zongru; Hu, Changwei; Wu, Hong; Zhang, Yicong; Liu, Xiaochuan; Wang, Wenliang; Wang, Junjie; Hu, Zhenquan; Wang, Aoli; Huang, Tao; Liu, Qingwang; Wang, Wei; Wang, Li; Wang, Qianqian; Ren, Tao; Li, Lili; Xia, Ruixiang; Ge, Jian; Liu, Jing

doi:10.1016/j.ejmech.2018.10.007

Cited by 9 publications

(1 citation statement)

References 27 publications

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“…Olverembatinib (GZD824), a pyrazolopyridine-diarylamide conjugate, was developed from ponatinib as a potent BCR-ABL T315I inhibitor with a favourable safety profile 16 . The indazole derivative CHMFL-ABL-121 is a type-II inhibitor derived from axitinib with an IC 50 value of 0.2 nM against BCR-ABL T315I 17 . The ureidobenzothiazole HS-438 was discovered by Park et al.…”

Section: Introductionmentioning

confidence: 99%

Overcoming the imatinib-resistant BCR-ABL mutants with new ureidobenzothiazole chemotypes endowed with potent and broad-spectrum anticancer activity

El-Damasy

Jin

Park

et al. 2023

Journal of Enzyme Inhibition and Medicinal Chemistry

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The design of kinase inhibitors targeting the oncogenic kinase BCR-ABL constitutes a promising paradigm for treating chronic myeloid leukaemia (CML). Nevertheless, the efficacy of imatinib, the first FDA-approved targeted therapy for CML, is curbed by the emergence of resistance. Herein, we report the identification of the 2-methoxyphenyl ureidobenzothiazole AK-HW-90 (2b) as a potent pan-BCR-ABL inhibitor against imatinib-resistant mutants, particularly T315I. A concise array of six compounds 2a – f was designed based on our previously reported benzothiazole lead AKE-5l to improve its BCR-ABL T315I inhibitory activity. Replacing the 6-oxypicolinamide moiety of AKE-5l with o -methoxyphenyl and changing the propyl spacer with phenyl afforded 2a and AK-HW-90 (2b) with IC 50 values of 2.0 and 0.65 nM against BCR-ABL T315I , respectively. AK-HW-90 showed superior anticancer potency to imatinib against multiple cancer cells (NCI), including leukaemia K-562. The obtained outcomes offer AK-HW-90 as a promising candidate for the treatment of CML and other types of cancer.

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Section: Introductionmentioning

confidence: 99%