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Identification of a new family of pyrazolo[3,4-d]pyrimidine derivatives as multitarget Fyn-Blk-Lyn inhibitors active on B- and T-lymphoma cell lines.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2019 Nov 01; Vol. 181, pp. 111545. Date of Electronic Publication: 2019 Jul 18. - Publication Year :
- 2019
-
Abstract
- Abnormal activation of B-cell receptor (BCR) signaling plays a key role in the development of lymphoid malignancies, and could be reverted by the simultaneous inhibition of Lyn, Fyn and Blk, three members of the Src family kinase (SFK). Fyn and Blk are also promising targets for the treatment of some forms of T-cell non-Hodgkin lymphoma which point to the druggability of SFKs for the treatment of these cancers. We recently identified Si308 as a potent Fyn inhibitor, while preliminary data showed that it might also inhibit Lyn and Blk. Here, molecular modelling studies were coupled with enzymatic assays to further investigate the effect of Si308 on Lyn and Blk. A small library of pyrazolo[3,4-d]pyrimidines structurally related to Si308 was synthesized and tested on human lymphoma cell lines. Compound 2h emerged as a new multitarget inhibitor of Lyn, Fyn and Blk endowed with remarkable antiproliferative effects on human B and T lymphoma cell lines. Its favorable ADME properties make the compound suitable for further developments.<br /> (Copyright © 2019. Published by Elsevier Masson SAS.)
- Subjects :
- Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Cell Cycle drug effects
Cell Proliferation drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Lymphoma, T-Cell metabolism
Lymphoma, T-Cell pathology
Molecular Structure
Protein Kinase Inhibitors chemical synthesis
Protein Kinase Inhibitors chemistry
Protein-Tyrosine Kinases antagonists & inhibitors
Protein-Tyrosine Kinases metabolism
Proto-Oncogene Proteins c-fyn metabolism
Pyrazoles chemical synthesis
Pyrazoles chemistry
Pyrimidines chemical synthesis
Pyrimidines chemistry
Structure-Activity Relationship
Tumor Cells, Cultured
src-Family Kinases metabolism
Antineoplastic Agents pharmacology
Lymphoma, T-Cell drug therapy
Protein Kinase Inhibitors pharmacology
Proto-Oncogene Proteins c-fyn antagonists & inhibitors
Pyrazoles pharmacology
Pyrimidines pharmacology
src-Family Kinases antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 181
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 31400706
- Full Text :
- https://doi.org/10.1016/j.ejmech.2019.07.048