In Silico Identification and Biological Evaluation
of Novel Selective Serum/Glucocorticoid-Inducible Kinase 1 Inhibitors
Based on the Pyrazolo-Pyrimidine Scaffold
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Abstract
The
serum/glucocorticoid-inducible kinase 1 (Sgk1) has demonstrated
antiapoptotic function and the capability to regulate cell survival,
proliferation, and differentiation. A pivotal role of Sgk1 in carcinogenesis
and in resistance to anticancer therapy has been suggested. With the
aim of identifying new Sgk1 modulators, 322 pyrazolo-pyrimidine derivatives
have been virtually screened with respect to a crystallographic model
of Sgk1. The top five ranked compounds have been evaluated demonstrating
Sgk1 inhibition in vitro and selectivity compared to RAC-alpha serine/threonine-protein
kinase (Akt1)