期刊
BIOORGANIC CHEMISTRY
卷 128, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2022.106071
关键词
Chronic myeloid leukemia; Src; Abl; Kinase inhibitors; Pyrazolo[3-d ]pyrimidines
资金
- AIRC Foundation for Cancer Research in Italy (Fondazione AIRC per la Ricerca sul Cancro, AIRC)
- Italian MIUR Project PRIN
- [23725]
- [20762]
- [24448]
- [2017SA5837_004]
This study identified a family of pyrazolo[3,4-d]pyrimidines as dual Src/Bcr-Abl inhibitors through a target-oriented approach. These compounds showed potential anti-leukemic activity and could be promising candidates for chronic myeloid leukemia (CML) therapy.
The Bcr-Abl tyrosine kinase (TK) is the molecular hallmark of chronic myeloid leukemia (CML). Src is another TK kinase whose involvement in CML was widely demonstrated. Small molecules active as dual Src/Bcr-Abl inhibitors emerged as effective targeted therapies for CML and a few compounds are currently in clinical use. In this study, we applied a target-oriented approach to identify a family of pyrazolo[3,4-d]pyrimidines as dual Src/ Bcr-Abl inhibitors as anti-leukemia agents. Considering the high homology between Src and Bcr-Abl, in-house Src inhibitors 8a-l and new analogue compounds 9a-n were screened as dual Src/Bcr-Abl inhibitors. The antiproliferative activity on K562 CML cells and the ADME profile were determined for the most promising compounds. Molecular modeling studies elucidated the binding mode of the inhibitors into the Bcr-Abl (wt) catalytic pocket. Compounds 8j and 8k showed nanomolar activities in enzymatic and cellular assays, together with favorable ADME properties, emerging as promising candidates for CML therapy. Finally, derivatives 9j and 9k, emerging as valuable inhibitors of the most aggressive Bcr-Abl mutation, T315I, constitute a good starting point in the search for compounds able to treat drug-resistant forms of CML. Overall, this study allowed us to identify more potent compounds than those previously reported by the group, marking a step forward in searching for new antileukemic agents.
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