Prostate cancer is the most commonly diagnosed cancer affecting men in the United States. The prostate is a hormone-dependent gland in which androgen hormones testosterone and dihydrotestosterone ...bind to and activate the androgen receptor, initiating nuclear translocation of androgen receptor and a subsequent signaling cascade. Due to the androgen dependency of the prostate, androgen deprivation therapies have emerged as first line treatment for aggressive prostate cancer. Such therapies are effective until the point at which prostate cancer, through a variety of mechanisms including but not limited to generation of ligand-independent androgen receptor splice variants, or intratumoral androgen production, overcome hormone deprivation. These cancers are androgen ablation resistant, clinically termed castration resistant prostate cancer (CRPC) and remain incurable. First-generation antiandrogens established androgen receptor blockade as a therapeutic strategy, but these therapies do not completely block androgen receptor activity. Efficacy and potency have been improved by the development of second-generation antiandrogen therapies, which remain the standard of care for patients with CRPC. Four second-generation anti-androgens are currently approved by the Food and Drug Administration (FDA); abiraterone acetate, enzalutamide, and recently approved apalutamide and darolutamide. This review is intended to provide a thorough overview of FDA approved second-generation antiandrogen discovery, treatment application, strategies for combination therapy to overcome resistance, and an insight for the potential future approaches for therapeutic inhibition of androgen receptor.
Recent progress in understanding the molecular basis of cellular processes, identification of promising therapeutic targets and evolution of the regulatory landscape makes this an exciting and ...unprecedented time to be in the field of oncology drug development. However, high costs, long development timelines and steep rates of attrition continue to afflict the drug development process. Lack of predictive preclinical models is considered one of the key reasons for the high rate of attrition in oncology. Generating meaningful and predictive results preclinically requires a firm grasp of the relevant biological questions and alignment of the model systems that mirror the patient context. In doing so, the ability to conduct both forward translation, the process of implementing basic research discoveries into practice, as well as reverse translation, the process of elucidating the mechanistic basis of clinical observations, greatly enhances our ability to develop effective anticancer treatments. In this Review, we outline issues in preclinical-to-clinical translatability of molecularly targeted cancer therapies, present concepts and examples of successful reverse translation, and highlight the need to better align tumour biology in patients with preclinical model systems including tracking of strengths and weaknesses of preclinical models throughout programme development.
RIO (right open reading frame) family of kinases including RIOK1, RIOK2 and RIOK3 are known for their role in the ribosomal biogenesis. Dysfunction of RIO kinases have been implicated in ...malignancies, including acute myeloid leukemia, glioma, breast, colorectal, lung and prostatic adenocarcinoma suggesting RIO kinases as potential targets in cancer. In vitro, in vivo and clinical studies have demonstrated that RIO kinases are overexpressed in various types of cancers suggesting important roles in tumorigenesis, especially in metastasis. In the context of malignancies, RIO kinases are involved in cancer-promoting pathways including AKT/mTOR, RAS, p53 and NF-κB and cell cycle regulation. Here we review the role of RIO kinases in cancer development emphasizing their potential as therapeutic target and encouraging further development and investigation of inhibitors in the context of cancer.
Cannabis elicits its mood-enhancing and analgesic effects through the cannabinoid receptor 1 (CB1), a G protein-coupled receptor (GPCR) that signals primarily through the adenylyl cyclase-inhibiting ...heterotrimeric G protein Gi. Activation of CB1-Gi signaling pathways holds potential for treating a number of neurological disorders and is thus crucial to understand the mechanism of Gi activation by CB1. Here, we present the structure of the CB1-Gi signaling complex bound to the highly potent agonist MDMB-Fubinaca (FUB), a recently emerged illicit synthetic cannabinoid infused in street drugs that have been associated with numerous overdoses and fatalities. The structure illustrates how FUB stabilizes the receptor in an active state to facilitate nucleotide exchange in Gi. The results compose the structural framework to explain CB1 activation by different classes of ligands and provide insights into the G protein coupling and selectivity mechanisms adopted by the receptor.
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•3 Å cryo-EM structure of the CB1-Gi complex bound to potent agonist MDMB-Fubinaca•MDMB-Fubinaca locks “toggle switch” residues F2003.36/W3566.48 in active conformation•Quantum mechanics calculations reveal the mechanism for the high affinity of Fubinaca•Molecular dynamic simulations reveal a path for ligand entry between TM1 and TM7
Looking at how a toxic, synthetic ligand locks cannabinoid receptor 1 into a signaling conformation points to ways to understand and modulate receptor activity.
Guanylate-binding protein 1 (GBP1) is a large GTPase of the dynamin superfamily involved in the regulation of membrane, cytoskeleton, and cell cycle progression dynamics. In many cell types, such as ...endothelial cells and monocytes, GBP1 expression is strongly provoked by interferon γ (IFNγ) and acts to restrain cellular proliferation in inflammatory contexts. In immunity, GBP1 activity is crucial for the maturation of autophagosomes infected by intracellular pathogens and the cellular response to pathogen-associated molecular patterns. In chronic inflammation, GBP1 activity inhibits endothelial cell proliferation even as it protects from IFNγ-induced apoptosis. A similar inhibition of proliferation has also been found in some tumor models, such as colorectal or prostate carcinoma mouse models. However, this activity appears to be context-dependent, as in other cancers, such as oral squamous cell carcinoma and ovarian cancer, GBP1 activity appears to anchor a complex, taxane chemotherapy resistance profile where its expression levels correlate with worsened prognosis in patients. This discrepancy in GBP1 function may be resolved by GBP1's involvement in the induction of a cellular senescence phenotype, wherein anti-proliferative signals coincide with potent resistance to apoptosis and set the stage for dysregulated proliferative mechanisms present in growing cancers to hijack GBP1 as a pro- chemotherapy treatment resistance (TXR) and pro-survival factor even in the face of continued cytotoxic treatment. While the structure of GBP1 has been extensively characterized, its roles in inflammation, TXR, senescence, and other biological functions remain under-investigated, although initial findings suggest that GBP1 is a compelling target for therapeutic intervention in a variety of conditions ranging from chronic inflammatory disorders to cancer.
There remains a need in clinics and research to have simple and sensitive detection systems that allow the detection and quantification of sugar markers of biomedical relevance such as sugars ...lactulose and mannitol for noninvasive gut permeability assessment. We have prepared a new class of boronic acid-appended naphthyl-pyridinium receptor compounds as chemosensors. These were studied for their ability to act as modular internal charge transfer (ICT) fluorescent probes or donor/acceptor pair ensembles where the receptor compound can act as a quencher for an anionic dye. As an ICT sensor, fluorescence intensity increased upon diol recognition, which stems from the neutralization of the pyridinium nitrogen that is perturbing the chromophoric properties. We found these ICT probes provide good sensitivity for disaccharide lactulose with low micromolar detection and quantification limits. In addition, their ability to form a non-fluorescent ground state complex with anionic reporter dyes, such as HPTS or TSPP, was examined as probes for various sugars. We have identified three receptor/quencher compounds with high quenching efficiency for anionic dyes. Subsequently, a range of sugars and sugar derivatives were tested for chemosenstivity of our probes. This study illustrates an approach for designing boronic acid-based chemoreceptors for the recognition and quantification of sugars and sugar derivatives.
ROS in breast carcinogenesis and TME reprogramming. ROS promotes carcinogenesis by damaging proteins, membrane lipids, and nucleic acids. They also promote reprogramming of cancer, stromal and immune ...cells by various mechanisms. Therapeutic strategies based on ROS modulation such as phytochemicals, chemotherapeutics, gene therapy, nanotherapy, and immune therapy can target the TME and reduces breast cancer metastasis.
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•ROS promote the reprogramming of breast TME cells by various mechanisms.•They promote genetic and epigenetic changes, metastasis, and drug resistance.•ROS mediate TME regulation by microRNA, exosomes, and autophagy.•Phytochemical responsive ROS target TME signaling pathways.•Chemotherapeutic responsive ROS enhance antitumor immunity.
Increases in Reactive oxygen species (ROS) have been reported in breast tumors and their surrounding tumor microenvironment (TME) cells. ROS are critical factors in breast TME as they ensure bidirectional communication among various components and mediate multi-faceted roles in tumor progression and metastasis. This paper presents a detailed and comprehensive review of the studies exploring ROS and various forms of oxidative stress in cancer progression, specifically breast cancer (BC), its microenvironment and associated cell types. The paper focuses on several diverse aspects of cellular and molecular biology of cancer, with pharmacological implications of phytochemicals in BC. We also describe the role of ROS in the genetic and epigenetic reprogramming of the TME, metastasis, and drug resistance as well as regulators of BC TME. Additionally, we discuss ROS-mediated TME therapy and the therapeutic conundrum of breast TME. These contributions could prompt the development of personalized anti-cancer drugs for the treatment of highly complex and aggressive BCs.
Highly efficient and chemoselective transfer hydrogenation of aldehydes has been achieved using polypyridyl iridium(III) catalysts in aqueous ethanol, with sodium formate as the hydride source. ...Successful reduction of acidic and hydroxy groups containing aldehydes can be achieved in basic and acidic reaction conditions, demonstrating the efficiency of the catalyst in a broad pH range with high conversion rates under microwave irradiation.
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•Highly efficient polypyridyl iridium(III) based catalysts.•Effective at a broad pH range for chemoselective reduction.•Catalysts are air stable, easy to prepare.•Method is applicable for a wide range of substrates.•These catalysts are capable of reducing all 2-, 3- and 4-carboxy benzaldehydes at different pH.
Iridium-catalyzed transfer hydrogenation (TH) of carbonyl compounds using HCOOR (R = H, Na, NH4) as a hydrogen source is a pivotal process as it provides the clean process and is easy to execute. However, the existing highly efficient iridium catalysts work at a narrow pH; thus, does not apply to a wide variety of substrates. Therefore, the development of a new catalyst which works at a broad pH range is essential as it can gain a broader scope of utilization. Here we report highly efficient polypyridyl iridium(III) catalysts, Ir(tpy)(L)Cl(PF6)2 {where tpy = 2,2′:6′,2′'-Terpyridine, L = phen (1,10-Phenanthroline), Me2phen (4,7-Dimethyl-1,10-phenanthroline), Me4phen (3,4,7,8-Tetramethyl-1,10-phenanthroline), Me2bpy (4,4′-Dimethyl-2–2′-dipyridyl)} for the chemoselective reduction of aldehydes to alcohols in aqueous ethanol and sodium formate as the hydride source. The reaction can be carried out efficiently in broad pH ranges, from pH 6 to 11. These catalysts are air stable, easy to prepare using commercially available starting materials, and are highly applicable for a wide range of substrates, such as electron-rich or deficient (hetero)arenes, halogens, phenols, alkoxy, ketones, esters, carboxylic acids, cyano, and nitro groups. Particularly, acid and hydroxy groups containing aldehydes were reduced successfully in basic and acidic reaction conditions, demonstrating the efficiency of the catalyst in a broad pH range with high conversion rates under microwave irradiation.
The anti-cancer activity and cytotoxicity of imidazolium-based ionic liquids has been determined for the first time via NCI’s in vitro 60 human tumor cell lines. The preliminary SAR showed that the ...chain length of alkyl substitution at N-3 position of imidazole ring plays crucial role towards anti-tumor activity and cytotoxicity of these ionic liquids.
The anti-cancer activity and cytotoxicity of imidazolium-based ionic liquids has been determined for the first time via NCI’s in vitro 60 human tumor cell lines. The preliminary SAR showed that the chain length of alkyl substitution at N-3 position of imidazole ring plays crucial role towards anti-tumor activity and cytotoxicity of these ionic liquids. The ionic liquids with alkyl substitution of C-12 chain length were found to be effective against all 60 tumor cell lines and show very low cytotoxicity in most of the cases. Further increase in chain length resulted in enhanced growth inhibition of tumor cell lines as well as high cytotoxicity. Interestingly, active compounds 1-dodecyl-3-methylimidazolium chloride (
8), 1-dodecyl-3-methylimidazolium tetrafluoroborate (
9), 1-hexadecyl-3-methylimidazoium chloride (
10), 1-octadecyl-3-methylimidazolium chloride (
11), 1-octadecyl-3-methylimidazolium hexafluorophosphate (
12), 1-octadecyl-3-methylimidazolium bis(triflic)imide (
13) and 1-octadecyl-3-methylimidazolium tris(pentafluoroethyl)trifluorophosphate (
14) were highly active against leukemia cell lines, especially compounds
13 and
14 where the cytotoxicity was also very low as given by LC
50 >100
μM in all six leukemia cell lines.
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