Identification of GZD824 as an orally bioavailable inhibitor that targets phosphorylated and nonphosphorylated breakpoint cluster region-Abelson (Bcr-Abl) kinase and overcomes clinically acquired mutation-induced resistance against imatinib
Bcr-Abl(T315I) mutation-induced imatinib resistance remains a major challenge for clinical management of chronic myelogenous leukemia (CML). Herein, we report GZD824 (10a) as a novel orally bioavailable inhibitor against a broad spectrum of Bcr-Abl mutants including T315I. It tightly bound to Bcr-Abl(WT) and Bcr-Abl(T315I) with K(d) values of 0.32 and 0.71 nM, respectively, and strongly inhibited the kinase functions with nanomolar IC(50) values. The compound potently suppressed proliferation of Bcr-Abl-positive K562 and Ku812 human CML cells with IC(50) values of 0.2 and 0.13 nM, respectively. It also displayed good oral bioavailability (48.7%), a reasonable half-life (10.6 h), and promising in vivo antitumor efficacy. It induced tumor regression in mouse xenograft tumor models driven by Bcr-Abl(WT) or the mutants and significantly improved the survival of mice bearing an allograft leukemia model with Ba/F3 cells harboring Bcr-Abl(T315I). GZD824 represents a promising lead candidate for development of Bcr-Abl inhibitors to overcome acquired imatinib resistance.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2013 |
|---|---|
| Erschienen: |
2013 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:56 |
|---|---|
| Enthalten in: |
Journal of medicinal chemistry - 56(2013), 3 vom: 14. Feb., Seite 879-94 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Ren, Xiaomei [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 19.04.2013 Date Revised 01.04.2022 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1021/jm301581y |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM224029657 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM224029657 | ||
| 003 | DE-627 | ||
| 005 | 20231224062023.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231224s2013 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1021/jm301581y |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0746.xml |
| 035 | |a (DE-627)NLM224029657 | ||
| 035 | |a (NLM)23301703 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Ren, Xiaomei |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Identification of GZD824 as an orally bioavailable inhibitor that targets phosphorylated and nonphosphorylated breakpoint cluster region-Abelson (Bcr-Abl) kinase and overcomes clinically acquired mutation-induced resistance against imatinib |
| 264 | 1 | |c 2013 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 19.04.2013 | ||
| 500 | |a Date Revised 01.04.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Bcr-Abl(T315I) mutation-induced imatinib resistance remains a major challenge for clinical management of chronic myelogenous leukemia (CML). Herein, we report GZD824 (10a) as a novel orally bioavailable inhibitor against a broad spectrum of Bcr-Abl mutants including T315I. It tightly bound to Bcr-Abl(WT) and Bcr-Abl(T315I) with K(d) values of 0.32 and 0.71 nM, respectively, and strongly inhibited the kinase functions with nanomolar IC(50) values. The compound potently suppressed proliferation of Bcr-Abl-positive K562 and Ku812 human CML cells with IC(50) values of 0.2 and 0.13 nM, respectively. It also displayed good oral bioavailability (48.7%), a reasonable half-life (10.6 h), and promising in vivo antitumor efficacy. It induced tumor regression in mouse xenograft tumor models driven by Bcr-Abl(WT) or the mutants and significantly improved the survival of mice bearing an allograft leukemia model with Ba/F3 cells harboring Bcr-Abl(T315I). GZD824 represents a promising lead candidate for development of Bcr-Abl inhibitors to overcome acquired imatinib resistance | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 650 | 7 | |a Benzamides |2 NLM | |
| 650 | 7 | |a Piperazines |2 NLM | |
| 650 | 7 | |a Protein Kinase Inhibitors |2 NLM | |
| 650 | 7 | |a Pyrazoles |2 NLM | |
| 650 | 7 | |a Pyrimidines |2 NLM | |
| 650 | 7 | |a Imatinib Mesylate |2 NLM | |
| 650 | 7 | |a 8A1O1M485B |2 NLM | |
| 650 | 7 | |a Protein-Tyrosine Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.10.1 |2 NLM | |
| 650 | 7 | |a Fusion Proteins, bcr-abl |2 NLM | |
| 650 | 7 | |a EC 2.7.10.2 |2 NLM | |
| 650 | 7 | |a olverembatinib |2 NLM | |
| 650 | 7 | |a KV1M7Q3CBP |2 NLM | |
| 700 | 1 | |a Pan, Xiaofen |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Zhang |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Deping |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Xiaoyun |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yupeng |e verfasserin |4 aut | |
| 700 | 1 | |a Wen, Donghai |e verfasserin |4 aut | |
| 700 | 1 | |a Long, Huoyou |e verfasserin |4 aut | |
| 700 | 1 | |a Luo, Jinfeng |e verfasserin |4 aut | |
| 700 | 1 | |a Feng, Yubing |e verfasserin |4 aut | |
| 700 | 1 | |a Zhuang, Xiaoxi |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Fengxiang |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Jianqi |e verfasserin |4 aut | |
| 700 | 1 | |a Leng, Fang |e verfasserin |4 aut | |
| 700 | 1 | |a Lang, Xingfen |e verfasserin |4 aut | |
| 700 | 1 | |a Bai, Yang |e verfasserin |4 aut | |
| 700 | 1 | |a She, Miaoqin |e verfasserin |4 aut | |
| 700 | 1 | |a Tu, Zhengchao |e verfasserin |4 aut | |
| 700 | 1 | |a Pan, Jingxuan |e verfasserin |4 aut | |
| 700 | 1 | |a Ding, Ke |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of medicinal chemistry |d 1963 |g 56(2013), 3 vom: 14. Feb., Seite 879-94 |w (DE-627)NLM000006602 |x 1520-4804 |7 nnns |
| 773 | 1 | 8 | |g volume:56 |g year:2013 |g number:3 |g day:14 |g month:02 |g pages:879-94 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1021/jm301581y |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 56 |j 2013 |e 3 |b 14 |c 02 |h 879-94 | ||