The small molecule SI113 hinders epithelial‐to‐mesenchymal transition and subverts cytoskeletal organization in human cancer cells

Abstract

The small molecule SI113 is an inhibitor of the kinase activity of SGK1, a key biological regulator acting on the PI3K/mTOR signal transduction pathway. Several studies demonstrate that this compound is able to strongly restrain cancer growth in vitro and in vivo, alone or in associative antineoplastic treatments, being able to elicit an autophagic response, either cytotoxic or cytoprotective. To elucidate more exhaustively the molecular mechanisms targeted by SI113, we performed activitybased protein profiling (ABPP) proteomic analysis using a kinase enrichment procedure. This technique allowed the identification via mass spectrometry of novel targets of this compound, most of them involved in functions concerning cell motility and cytoskeletal architecture. Using a glioblastoma multiforme, hepatocarcinoma and colorectal carcinoma cell line, we recognized an inhibitory effect of SI113 on cell migration, invading, and epithelial-to-mesenchymal transition. In addition, these cancer cells, when exposed to this compound, showed a remarkable subversion of the cytoskeletal architecture characterized by F-actin destabilization, phospho-FAK delocalization, and tubulin depolimerization. These results were definitely concordant in attributing to SI113 a key role in hindering cancer cell malignancy and, due to its negligible in vivo toxicity, can sustain performing a Phase I clinical trial to employ this drug in associative cancer therapy. K E Y W O R D Sactivity-based protein profiling (ABPP), cytoskeleton, epithelial-to-mesenchymal transition, kinase inhibitors, SI113

Synthesis and Antibacterial Evaluation of New Pyrazolo[3,4-d]pyrimidines Kinase Inhibitors

“…In particular, compound 4 was able to halve E. coli bacterial growth (Figure 4) at the lowest concentration tested (50 µg/mL). For compounds 2 (SI113) and 3, which here showed comparable antimicrobial activity against both the bacterial strains, we have previously reported their anticancer activity in vitro and in vivo [27,35] (as discussed above). Interestingly, the SI113-dependent inhibition of SGK1 was also demonstrated to enhance cytotoxic autophagy in GBM cell lines, leading to cancers cell death [30].…”

“…Our preliminary study in an antimicrobial context revealed the strong antibacterial potential of pyrazolo [3,4-d]pyrimidines already active as kinase inhibitors [35,45] and endowed with antiproliferative properties. In particular, six compounds were identified for their bacteriostatic activity against Gram-positive S. aureus and Gram-negative E. coli.…”

The Emerging Role of SGK1 (Serum- and Glucocorticoid-Regulated Kinase 1) in Major Depressive Disorder: Hypothesis and Mechanisms

“…Interestingly, a new inhibitor for SGK1, named SI113, has been developed. In cellular models as well as in murine models, SI113 has amply demonstrated potential antineoplastic capacity, showing a very low toxicity profile ( Abbruzzese et al, 2017 , 2019 ; Catalogna et al, 2017 ; Matteoni et al, 2019 ). Pharmacological ADME (absorption, distribution, metabolism, and excretion) studies have corroborated the ability of SI113 to cross the blood-brain barrier, thus opening the possibility of a rational use of the molecule, even in psychiatric and neurological diseases ( Talarico et al, 2016b ).…”

The prospect of serum and glucocorticoid-inducible kinase 1 (SGK1) in cancer therapy: a rising star

“…Inhibition of SGK1 decreases the mesenchymal markers N-cadherin, vimentin, and focal adhesion kinase, and reduces the cell motility and invasion abilities. 18 As noted previously, mAR demonstrates strong antioxidant and antitumorigenic effects, which are mediated by vinculin phosphorylation and actin reorganization. Transfection with a constitutively active SGK1 mutant effectively dephosphorylates the cell-adhesion protein vinculin and enhances cell motility.…”

“… 1 , 3 , 14 , 15 SGK1 has been previously reported in hypertension, diabetes, hypercoagulability, and autoimmune disease. 5 , 16 , 17 A growing number of recent studies reveal a role for SGK1 in human tumors such as glioblastoma, 18 – 20 breast, 21 – 25 colorectal, 26 – 28 prostate, 29 – 31 thyroid, 32 ovarian, 33 myeloma, 11 and non-small cell lung cancer 34 ( Figure 1 ).…”