Abstract:A structural investigation on the isoxazole scaffold led to the discovery of 3,4-isoxazolediamide compounds endowed with potent Hsp90 inhibitory properties. We have found that compounds possessing a nitrogen atom directly attached to the C-4 heterocycle ring possess in vitro Hsp90 inhibitory properties at least comparable to those of the structurally related 4,5-diarylisoxazole derivatives. A group of compounds from this series of diamides combine potent binding affinity and cell growth inhibitory activity in … Show more
“…Hsp90 inhibitors are classified into several categories containing natural inhibitors (geldanamycin, GM (1), and radicicol (2)), reclaimed analogues of GM (17-AAG (3) and 17-DMAG (4), synthetic inhibitors (purine (PU3 (5)), pyrazole (6), indazole (7), aminoquinolines (SID: 24724290 (8)) and isoxazole (9) that are shown in Fig. 2 [8–11]. Some of these inhibitors, such as the reclaimed analogue of geldanamycin (17-AAG), carbazol-4-one benzamide derivative (SNX-5422) and isoxazole derivative (NVP-AUY922, currently known as Luminespib), have been assessed in humans (Fig.…”
Section: Introductionmentioning
confidence: 99%
“…Among the different azaheterocyclic ring systems, the isoxazole scaffold is one of the most promising heterocyclic systems [12]. Baruchello and coworkers in 2011 synthesized novel 3, 4-isoxazolediamides as potent inhibitors of Hsp90 [8]. Fig.…”
BackgroundHeat shock protein90 (Hsp90) are overexpressed in tumor cells, so the inhibition of the Hsp90 ATPase activity would be a significantly effective strategy in cancer therapy.MethodsIn the current study, 3,4-isoxazolediamide derivatives were suggested as an Hsp90 inhibitor for anti-cancer therapy. Multiple linear regression (MLR) and genetic algorithm of partial least square (GA-PLS) methods were performed to build models to predict the inhibitory activity of Hsp90. The leave-one out (LOO) cross-validation and Y-randomization tests were performed to models’ validation. The new ligands were monitored by applicability domain. Molecular docking studies were also conducted to evaluate the mode of interaction of these compounds with Hsp90. Identification of the likely pathways into the active site pocket and the involved residues were performed by CAVAER 3.0.1 software. According to QSAR models and docking analysis, three new compounds were predicted. 50 ns molecular dynamic simulation was performed for the strongest synthesized compound and the best predicted compound in terms of binding energy and interactions between ligand and protein.ResultsThe made models showed the significance of size, shape, symmetry, and branching of molecules in inhibitory activities of Hsp90. Docking studies indicated that two hydroxyl groups in the resorcinol ring were important in interacting with Asp93 and the orientation of these groups was related to substitution of different R1 groups. Comparing of molecular dynamic simulation (MDs) results shows that new compound perched in active site with lower binding energy than the best synthesized compound.ConclusionThe QSAR and docking analyses shown to be beneficial tools in the proposal of anti-cancer activities and a leader to the synthesis of new Hsp90 inhibitors based 3,4-isoxazolediamide. The MDs confirmed that predicted ligand is steady in the Hsp90 active sites.Graphical Abstract
“…Hsp90 inhibitors are classified into several categories containing natural inhibitors (geldanamycin, GM (1), and radicicol (2)), reclaimed analogues of GM (17-AAG (3) and 17-DMAG (4), synthetic inhibitors (purine (PU3 (5)), pyrazole (6), indazole (7), aminoquinolines (SID: 24724290 (8)) and isoxazole (9) that are shown in Fig. 2 [8–11]. Some of these inhibitors, such as the reclaimed analogue of geldanamycin (17-AAG), carbazol-4-one benzamide derivative (SNX-5422) and isoxazole derivative (NVP-AUY922, currently known as Luminespib), have been assessed in humans (Fig.…”
Section: Introductionmentioning
confidence: 99%
“…Among the different azaheterocyclic ring systems, the isoxazole scaffold is one of the most promising heterocyclic systems [12]. Baruchello and coworkers in 2011 synthesized novel 3, 4-isoxazolediamides as potent inhibitors of Hsp90 [8]. Fig.…”
BackgroundHeat shock protein90 (Hsp90) are overexpressed in tumor cells, so the inhibition of the Hsp90 ATPase activity would be a significantly effective strategy in cancer therapy.MethodsIn the current study, 3,4-isoxazolediamide derivatives were suggested as an Hsp90 inhibitor for anti-cancer therapy. Multiple linear regression (MLR) and genetic algorithm of partial least square (GA-PLS) methods were performed to build models to predict the inhibitory activity of Hsp90. The leave-one out (LOO) cross-validation and Y-randomization tests were performed to models’ validation. The new ligands were monitored by applicability domain. Molecular docking studies were also conducted to evaluate the mode of interaction of these compounds with Hsp90. Identification of the likely pathways into the active site pocket and the involved residues were performed by CAVAER 3.0.1 software. According to QSAR models and docking analysis, three new compounds were predicted. 50 ns molecular dynamic simulation was performed for the strongest synthesized compound and the best predicted compound in terms of binding energy and interactions between ligand and protein.ResultsThe made models showed the significance of size, shape, symmetry, and branching of molecules in inhibitory activities of Hsp90. Docking studies indicated that two hydroxyl groups in the resorcinol ring were important in interacting with Asp93 and the orientation of these groups was related to substitution of different R1 groups. Comparing of molecular dynamic simulation (MDs) results shows that new compound perched in active site with lower binding energy than the best synthesized compound.ConclusionThe QSAR and docking analyses shown to be beneficial tools in the proposal of anti-cancer activities and a leader to the synthesis of new Hsp90 inhibitors based 3,4-isoxazolediamide. The MDs confirmed that predicted ligand is steady in the Hsp90 active sites.Graphical Abstract
“…Given this precedent, we planned to identify novel Hsp90 inhibitors with a superior pharmacological and tolerability profile. We previously identified a new class of 3,4-isoxazolediamides (17), where the compound SST0116CL1 was selected as a potential new drug candidate, unrelated to the ansamycin class of natural products. We chose to investigate molecules with innovative changes and to assess the benefits of such changes through well-focused in vivo studies, based on suitable tumor models.…”
Section: Discussionmentioning
confidence: 99%
“…We have previously described the discovery of a novel series of 3,4-isoxazolediamides based Hsp90 inhibitors which were shown to have a very interesting activity both in vitro and in vivo (17). In particular, within this group, we selected the compound SST0116CL1 as a synthetic, new chemical entity designed to potently inhibit Hsp90.…”
4-Amino substituted resorcino-isoxazole (SST0116CL1) (property of Sigma-Tau Research Switzerland S.A.) is a potent, second generation, small-molecule heat shock protein 90 inhibitor (Hsp90i). SST0116CL1 binds to the ATP binding pocket of Hsp90, and interferes with Hsp90 chaperone function thus resulting in client protein degradation and tumor growth inhibition. The aim of the study was to assess SST0116CL1 in various solid and haematological tumors. The antitumor properties of SST0116CL1 were assessed using in vitro cell proliferation and client protein degradation assays and in vivo different tumor xenograft models. Pharmacokinetic (PK) data were also generated in tumor-bearing mice to gain an understanding of optimal dosing schedules and regimens. SST0116CL1 was shown to inhibit recombinant Hsp90α and to induce the destabilization of different client proteins, often overexpressed and constitutively activated in different types of hematological or solid human tumors. In preclinical in vivo studies, it was revealed to induce antitumor effects in murine models of leukemia and of gastric and ovarian carcinoma. A modulation of PD biomarkers in terms of downregulation of Hsp90 client proteins in tumor-bearing mice was found. SST0116CL1 is a new clinical candidate for cancer therapy. The antitumor property of SST0116CL1, likely due to direct inhibition of the Hsp90 enzymatic activity, may prove to be a critical attribute as the compound enters phase I clinical trials.
“…1). [26][27][28][29] Based on these results, we designed and synthesized a series of new alkynes-linked isoxazole scaffolds to investigate their inhibitory activities for human HSP90a and HSP90b proteins, and further to determine their anti-proliferative activity against tumor cell lines. While maintaining the interactions of the resorcinol OH groups and C-3 amide, we speculated that the introduction of an alkynes group at C-4, as shown for compound 19a (Figs.…”
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