A Novel Decalin-Based Bicyclic Scaffold for FKBP51-Selective Ligands.

Selective inhibition of FKBP51 has emerged as possible novel treatment for diseases like major depressive disorder, obesity, chronic pain, and certain cancers. The current FKBP51 inhibitors are rather large, flexible, and have to be further optimized. By using a structure-based rigidification strategy, we hereby report the design and synthesis of a novel promising bicyclic scaffold for FKBP51 ligands. The structure-activity analysis revealed the decalin scaffold as the best moiety for the selectivity-enabling subpocket of FBKP51. The resulting compounds retain high potency for FKBP51 and excellent selectivity over the close homologue FKBP52. With the cocrystal structure of an advanced ligand in this novel series, we show how the decalin locks the key selectivity-inducing cyclohexyl moiety of the ligand in a conformation typical for FKBP51-selective binding. The best compound 29 produces cell death in a HeLa-derived KB cell line, a cellular model of cervical adenocarcinoma, where FKBP51 is highly overexpressed. Our results show how FKBP51 inhibitors can be rigidified and extended while preserving FKBP51 selectivity. Such inhibitors might be novel tools in the treatment of human cancers with deregulated FKBP51.

TRAF2 and FKBP51 as possible markers for identification of suitable melanoma tumors for tumor necrosis factor-α inhibition.

Tumor necrosis factor-α (TNF-α) is a pleiotropic cytokine, whose role in melanoma is controversial. Although high-dose TNF-α is approved for the treatment of patients with in transit-metastatic melanoma confined to the limb, diverse preclinical models of melanoma have shown that TNF-α can induce cell invasion. Biomarkers that can differentiate between the dual role of TNF-α are needed. TRAF2 is critical to TNF receptor-induced activation of nuclear factor-κB (NF-κB), allowing shifting from death to survival-signaling cascades. The large immunophilin FKBP51 acts as a scaffold and catalyst in the IκB kinase complex assembly and activation. Here, using microscopy and an electrophoretic mobility-shift assay, we provide further evidence in support of the essential role of FKBP51 in sustaining the TNF-α NF-κB signaling in melanoma. Through the cross-linking reaction with the chemical linker disuccinimidyl glutarate, we show that a direct interaction occurs between FKBP51 and TRAF2 in melanoma cells. Immunohistochemistry of tumor samples from 24 patients with cutaneous melanomas showed a correlation between the expressions of the two proteins. Given the association of FKBP51 and TRAF2 with TNF-α-induced NF-κB signaling and their correlation in tumor samples, we propose that the two proteins can be exploited as useful markers for the identification of those melanoma tumors that can benefit from TNF-α inhibition. Future studies will address this hypothesis.

Molecular Aspects of FKBP51 that Enable Melanoma Dissemination.

FKBP51 (FKBP5 Official Symbol) is large molecular weight member of the FK506 binding protein family, a subfamily of the immunophilin proteins. FKBP51 exerts multiple biological functions in the cell, including modulation of steroid hormone response, immune regulation, cell proliferation, regulation of pAkt levels and control of NF-κB activation. Several lines of evidence support a role for this protein in cancer biology, especially in resistance to chemo- and radio-therapy. Recent research studies highlighted functions of FKBP51 in promoting the epithelial to mesenchymal transition (EMT) transdifferentiation program in melanoma. This process, which is classically regulated by Transforming Growth Factor (TGF)-ß, enables cancer cells to disseminate from primary tumors and spread to distant locations, acquiring resistance to therapy and self-renewal capability. This last, in turn, is crucial to their subsequent expansion at sites of dissemination. The aim of the present article is to review recent literature data that involve FKBP51 in the mechanisms that switch the TGF-ß from a tumor suppressor to a pro-metastatic invader.

Left ventricular remodeling after primary coronary angioplasty in patients treated with abciximab or intracoronary adenosine.

BACKGROUND: Primary angioplasty is the best treatment of acute myocardial infarction but fails to achieve adequate myocardial reperfusion in 25% to 30% of patients, despite TIMI grade 3 flow. Drug treatment aimed at reducing the no-reflow phenomenon may improve myocardial salvage, thus preventing left ventricular remodeling. Our aim was to evaluate the impact of abciximab and adenosine on immediate angiographic results and on 6-month left ventricular remodeling. METHODS: Ninety consecutive patients undergoing primary angioplasty with coronary stenting were randomized in a sequential alternating fashion to standard abciximab treatment (ABCX) group, intracoronary adenosine distal to the occlusion (ADO) group, or neither (CTRL) group. All patients underwent a clinical and echocardiographic follow-up at 1 and 6 months. The primary end point was the prevalence of 6-month left ventricular remodeling. RESULTS: Baseline clinical, echocardiographic, and angiographic characteristics were similar. Mean final corrected TIMI frame count was 17 +/- 9, 16 +/- 12, and 23 +/- 11 frames in ABCX, ADO, and CTRL patients, respectively (P = .002). Angiographic no-reflow was observed in 7%, 13%, and 17% of ABCX, ADO, and CTRL patients, respectively (P > .20). At 6 months, left ventricular remodeling occurred in 7%, 30%, and 30% of ABCX, ADO, and CTRL patients, respectively (P = .045), with a percent increase in end-diastolic volume of 5% +/- 13%, 15% +/- 15%, and 12% +/- 18% (P = .04). CONCLUSIONS: During primary angioplasty, abciximab enhances myocardial reperfusion, translating into a reduced incidence of 6-month left ventricular remodeling. In contrast, adenosine administration improves angiographic results but does not prevent left ventricular remodeling.