Abstract:
:Fyn is a member of the Src-family of nonreceptor protein-tyrosine kinases. Its abnormal activity has been shown to be related to various human cancers as well as to severe pathologies, such as Alzheimer's and Parkinson's diseases. Herein, a structure-based drug design protocol was employed aimed at identifying novel Fyn inhibitors. Two hits from commercial sources (1, 2) were found active against Fyn with K(i) of about 2 μM, while derivative 4a, derived from our internal library, showed a K(i) of 0.9 μM. A hit-to-lead optimization effort was then initiated on derivative 4a to improve its potency. Slightly modifications rapidly determine an increase in the binding affinity, with the best inhibitors 4c and 4d having K(i)s of 70 and 95 nM, respectively. Both compounds were found able to inhibit the phosphorylation of the protein Tau in an Alzheimer's model cell line and showed antiproliferative activities against different cancer cell lines.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Tintori C,La Sala G,Vignaroli G,Botta L,Fallacara AL,Falchi F,Radi M,Zamperini C,Dreassi E,Dello Iacono L,Orioli D,Biamonti G,Garbelli M,Lossani A,Gasparrini F,Tuccinardi T,Laurenzana I,Angelucci A,Maga G,Schenone Sdoi
10.1021/acs.jmedchem.5b00140subject
Has Abstractpub_date
2015-06-11 00:00:00pages
4590-609issue
11eissn
0022-2623issn
1520-4804journal_volume
58pub_type
杂志文章abstract::Various semicarbazones derived from aryl aldehydes, phenylalkyl aldehydes, and phenylalkyl ketones as well as some related compounds were evaluated for anticonvulsant activity. Most of the compounds displayed anticonvulsant activity in the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) screens ...
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