Prostate cancer (PC) is the fifth leading cause of cancer death in men, and the androgen receptor (AR) represents the primary target for PC treatment, even though the disease frequently progresses ...toward androgen-independent forms. Most of the commercially available nonsteroidal antiandrogens show a common scaffold consisting of two aromatic rings connected by a linear or a cyclic spacer. By taking advantage of a facile, one-pot click chemistry reaction, we report herein the preparation of a small library of novel 1,4-substituted triazoles with AR antagonistic activity. Biological and theoretical evaluation demonstrated that the introduction of the triazole core in the scaffold of nonsteroidal antiandrogens allowed the development of small molecules with improved overall AR-antagonist activity. In fact, compound 14d displayed promising in vitro antitumor activity toward three different prostate cancer cell lines and was able to induce 60% tumor growth inhibition of the CW22Rv1 in vivo xenograft model. These results represent a step toward the development of novel and improved AR antagonists.
Prostate cancer is among the leading causes of cancer related death of men in the United States. The ERG gene fusion leading to overexpression of near full-length ERG transcript and protein ...represents most prevalent (50–65%) prostate cancer driver gene alterations. The ERG oncoprotein overexpression persists in approximately 35% of metastatic castration resistant prostate cancers. Due to the emergence of eventual refractoriness to second- and third-generation androgen axis-based inhibitors, there remains a pressing need to develop drugs targeting other validated prostate cancer drivers such as ERG. Here we report the new and more potent ERG inhibitor ERGi-USU-6 developed by structure–activity studies from the parental ERGi-USU. We have developed an improved procedure for the synthesis of ERGi-USU-6 and identified a salt formulation that further improves its activity in biological assays for selective targeting of ERG harboring prostate cancer cells.
The synthesis of novel pyrazolylnucleosides
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,
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,
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, and
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are described. The structures of the regioisomers were elucidated by using extensive NMR studies. The pyrazolylnucleosides
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and
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were ...screened for anticancer activities on sixty human tumor cell lines. The compound
showed good activity against 39 cancer cell lines. In particular, it showed significant inhibition against the lung cancer cell line Hop-92 (GI
9.3 µM) and breast cancer cell line HS 578T (GI
3.0 µM).
Surgical resection and radiotherapy are an effective treatment in many head and neck squamous cell carcinomas (HNSCC), but in others, the development of radiotherapy resistance limits treatment ...efficacy and permits disease progression. We developed a novel multiwell radiation dosing method to increase the throughput of our investigation of the activity of a novel podophyllotoxin SU093 in acting as a radiosensitizer in the HNSCC models FaDu and SCC-25. These in vitro studies showed that combining SU093 with 5 Grays ionizing radiation acted synergistically to increase HNSCC apoptosis and decrease its proliferation via inhibition of Nuclear factor, erythroid 2 like 2 (Nrf2), a key effector of the DNA damage response induced by ionizing radiation. Combined treatment reduced in vitro migration in a simulated wounding model while also promoting cell cycle arrest at the G2/M phase. These findings validate the potential of SU093 as a synergistic radiosensitizing agent for use in combination with localized radiotherapy in treatment resistant HNSCC.
Oncogenic activation of the ETS-related gene (
) by recurrent gene fusions (predominantly TMPRSS2-ERG) is one of the most validated and prevalent genomic alterations present in early stages of ...prostate cancer. In this study, we screened small-molecule libraries for inhibition of ERG protein in
harboring VCaP prostate cancer cells using an In-Cell Western Assay with the highly specific ERG-MAb (9FY). Among a subset of promising candidates, 1-2-Thiazolylazo-2-naphthol (NSC139021, hereafter ERGi-USU) was identified and further characterized. ERGi-USU selectively inhibited growth of ERG-positive cancer cell lines with minimal effect on normal prostate or endothelial cells or ERG-negative tumor cell lines. Combination of ERGi-USU with enzalutamide showed additive effects in inhibiting growth of VCaP cells. A screen of kinases revealed that ERGi-USU directly bound the ribosomal biogenesis regulator atypical kinase RIOK2 and induced ribosomal stress signature.
, ERGi-USU treatment inhibited growth of ERG-positive VCaP tumor xenografts with no apparent toxicity. Structure-activity-based derivatives of ERGi-USU recapitulated the ERG-selective activity of the parental compound. Taken together, ERGi-USU acts as a highly selective inhibitor for the growth of ERG-positive cancer cells and has potential for further development of ERG-targeted therapy of prostate cancer and other malignancies.
A highly selective small-molecule inhibitor of ERG, a critical driver of early stages of prostate cancer, will be imperative for prostate cancer therapy.
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In this study, a Cu
2+ chelate of the novel thiosemicarbazone NSC 689534 was evaluated for in vitro and in vivo anti-cancer activity. Results demonstrated that NSC 689534 activity (low micromolar ...range) was enhanced four- to fivefold by copper chelation and completely attenuated by iron. Importantly, once formed, the NSC 689534/Cu
2+ complex retained activity in the presence of additional iron or iron-containing biomolecules. NSC 689534/Cu
2+ mediated its effects primarily through the induction of ROS, with depletion of cellular glutathione and protein thiols. Pretreatment of cells with the antioxidant
N-acetyl-l-cysteine impaired activity, whereas NSC 689534/Cu
2+ effectively synergized with the glutathione biosynthesis inhibitor buthionine sulfoximine. Microarray analysis of NSC 689534/Cu
2+-treated cells highlighted activation of pathways involved in oxidative and ER stress/UPR, autophagy, and metal metabolism. Further scrutiny of the role of ER stress and autophagy indicated that NSC 689534/Cu
2+-induced cell death was ER-stress dependent and autophagy independent. Last, NSC 689534/Cu
2+ was shown to have activity in an HL60 xenograft model. These data suggest that NSC 689534/Cu
2+ is a potent oxidative stress inducer worthy of further preclinical investigation.
Guanylate-binding protein 1 (GBP1) is known as an interferon-γ-induced GTPase. Here, we used genetically modified ovarian cancer (OC) cells to study the role of GBP1. The data generated show that ...GBP1 inhibition constrains the clonogenic potential of cancer cells. In vivo studies revealed that GBP1 overexpression in tumors promotes tumor progression and reduces median survival, whereas GBP1 inhibition delayed tumor progression with longer median survival. We employed proteomics-based thermal stability assay (CETSA) on GBP1 knockdown and overexpressed OC cells to study its molecular functions. CETSA results show that GBP1 interacts with many members of the proteasome. Furthermore, GBP1 inhibition sensitizes OC cells to paclitaxel treatment via accumulated ubiquitinylated proteins where GBP1 inhibition decreases the overall proteasomal activity. In contrast, GBP1-overexpressing cells acquired paclitaxel resistance via boosted cellular proteasomal activity. Overall, these studies expand the role of GBP1 in the activation of proteasomal machinery to acquire chemoresistance.
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•GBP1 inhibition delays the ovarian cancer progression•Overexpression of GBP1 contributes to the development of paclitaxel resistance•GBP1 modulates the proteasomal activity in ovarian cancer cells
Pharmacology; Biochemistry; Molecular biology; Cancer; Proteomics
Novel piperidinyl-based sulfamide derivatives were designed and synthesized through various synthetic routes. Anticancer activities of these sulfamides were evaluated by phenotypic screening on ...National Cancer Institute's 60 human tumor cell lines (NCI-60). Preliminary screening at 10μM concentration showed that piperidinyl sulfamide aminoester 26 (NSC 749204) was sensitive to most of the cell lines in the panel. Further dose-response studies showed that 26 was highly selective for inhibition of colon cancer cell lines with minimum GI50=1.88μM for COLO-205 and maximum GI50=11.1μM for SW-620 cells. These newly synthesized sulfamides were also screening for their Tdp1 inhibition activity. Compound 18 (NSC 750706) showed significant inhibition of Tdp1 with IC50=23.7μM. Molecular-docking studies showed that 18 bind to Tdp1 in its binding pocket similar to a known Tdp1 inhibitor.
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Enhancing the immune microenvironment in cancer by targeting the nucleic acid sensors is becoming a potent therapeutic strategy. Among the nucleic acid sensors, activation of the RNA sensor Retinoic ...Acid-inducible Gene (RIG-I) using small hairpin RNAs has been shown to elicit powerful innate and adaptive immune responses. Given the challenges inherent in pharmacokinetics and delivery of RNA based agonists, we set out to discover small molecule agonists of RIG-I using a cell-based assay. To this end, we established and validated a robust high throughput screening assay based on a commercially available HEK293 reporter cell line with a luciferase reporter downstream of tandem interferon stimulated gene 54 (ISG54) promoter elements. We first confirmed that the luminescence in this cell line is dependent on RIG-I and the interferon receptor using a hairpin RNA RIG-I agonist. We established a 96-well and a 384-well format HTS based on this cell line and performed a proof-of-concept screen using an FDA approved drug library of 1,200 compounds. Surprisingly, we found two HDAC inhibitors Entinostat, Mocetinostat and the PLK1 inhibitor Volasertib significantly enhanced ISG-luciferase activity. This luminescence was substantially diminished in the null reporter cell line indicating the increase in signaling was dependent on RIG-I expression. Combination treatment of tumor cell lines with Entinostat increased RIG-I induced cell death in a mammary carcinoma cell line that is resistant to either Entinostat or RIG-I agonist alone. Taken together, our data indicates an unexpected role for HDAC1,-3 inhibitors in enhancing RIG-I signaling and highlight potential opportunities for therapeutic combinations.
A natural compound screen identified several anticancer compounds, among which azapodophyllotoxin (AZP) was found to be the most potent. AZP caused decreased viability of both mouse and human ...lymphoma and renal cell cancer (RCC) tumor-derived cell lines. Novel AZP derivatives were synthesized and screened identifying compound NSC750212 to inhibit the growth of both lymphoma and RCC both in vitro and in vivo. A nanoimmunoassay was used to assess the NSC750212 mode of action in vivo. On the basis of the structure of AZP and its mode of action, AZP disrupts tubulin polymerization. Through desorption electrospray ionization mass spectrometry imaging, NSC750212 was found to inhibit lipid metabolism. NSC750212 suppresses monoglycerol metabolism depleting lipids and thereby inhibits tumor growth. The dual mode of tubulin polymerization disruption and monoglycerol metabolism inhibition makes NSC750212 a potent small molecule against lymphoma and RCC.
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