Alcaro, S.

Greco, C.

Musumeci, F.

Ortuso, F.

Perrotti, N.

Schenone, S.

English

Schenone S.

Archivio istituzionale della ricerca - Università di Genova

La Giornata della Chimica Ligure Le attuali tendenze della ricerca chimica in Liguria    Sezione LiguriaSGK1 AS A NEW TARGET FOR ANTICANCER AGENTS: A HIT-TO-LEAD STUDY  F. Musumeci 1, C. Greco 1, S. Alcaro 2, F. Ortuso 2, N. Perrotti 2, S. Schenone 1  1Department of Pharmacy, University of Genoa, Viale Benedetto XV 3, Genoa, Italy 2Department of "Scienze della Salute", University "Magna Graecia" of Catanzaro, Viale Europa, Catanzaro, Italy francesca.musumeci@unige.it   The serum and glucocorticoid kinase (SGK) is a family of serine/threonine kinases which includes three isoforms, SGK1, SGK2 and SGK3. SGK1 recently appeared as an essential and non-redundant target in cancer therapy, being involved in the development and resistance of human tumours. Furthermore, SGK1 plays a critical role in metabolic syndrome. Nevertheless, only few SGK1 inhibitors have been reported in the literature to date [1]. In this context, we decided to virtually screen our library of pyrazolo[3,4-d]pyrimidines, originally synthesized to target the tyrosine kinases Src and Abl, in order to find potential SGK1 inhibitors. This in silico study led to the identification of a few promising compounds that have been tested on SGK1 and a small panel of kinases. Among these molecules, SI113 (Figure 1) shows an IC50 value of 600 nM on SGK1 and results quite selective for this kinase compared with AKT-1, Src and Abl [2]. SI113 possesses pro-apoptotic and anti-proliferative effects in different cancer cell lines, synergizing with radiotherapy in tumor killing [3,4]. Interestingly, SI113 inhibits tumour growth in hepatocarcinoma models in vitro and in vivo. Moreover, no side effects, e.g. weight loss, diarrhea, dermatitis, or signs of liver failure, appeared in SI113 treated mice [3]. Starting from these exciting results, we decided to start a hit-to-lead study aimed at discovering new SGK1 inhibitors endowed with a better activity than SI113 and a good pharmacokinetic profile. Here, we report an overview of the activity of the hit compound SI113 and an update on the work in progress on this new generation of derivatives 1 (Figure 1).  NN NNNHHOHNNN NNR1NHRNHR = aliphatic or aromatic amino groupsR1 = NHCH2CH2OH, N(CH2CH2OH)2,        morpholineX = H, halogen atoms1SI113X    Figure 1 - Structure of the hit compound SI113 and new generation of SGK1 inhibitors 1  References: [1] F. Lang, J. Voelkl. Therapeutic potential of serum and glucocorticoid inducible kinase inhibition. Expert Opin Investig Drugs, 22, 701 (2013). [2] F. Ortuso, R. Amato, A. Artese, et al. In silico identification and biological evaluation of novel selective serum/glucocorticoid-inducible kinase 1 inhibitors based on the pyrazolo-pyrimidine scaffold. J Chem Inf Model 54, 1828 (2014). [3] C. Talarico, L. D'Antona, D. Scumaci, et al. Preclinical model in HCC: the SGK1 kinase inhibitor SI113 blocks tumor progression in vitro and in vivo and synergizes with radiotherapy. Oncotarget, 6, 37511 (2015). [4] C. Talarico, V. Dattilo, L. D'Antona, et al. SI113, a SGK1 inhibitor, potentiates the effects of radiotherapy, modulates the response to oxidative stress and induces cytotoxic autophagy in human glioblastoma multiforme cells. Oncotarget, 7, 15868 (2016). 7

SGK1 as a new target for anticancer agents: a hit-to-lead study

https://iris.unige.it/bitstream/11567/895633/1/O5%29%20Giornata%20Chimica%20Ligure_Musumeci.pdf

SGK1 as a new target for anticancer agents: a hit-to-lead study

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Archivio istituzionale della ricerca - Università di Genova