Oncogenic Role of THOR, a Conserved Cancer/Testis Long Non-coding RNA.

Large-scale transcriptome sequencing efforts have vastly expanded the catalog of long non-coding RNAs (lncRNAs) with varying evolutionary conservation, lineage expression, and cancer specificity. Here, we functionally characterize a novel ultraconserved lncRNA, THOR (ENSG00000226856), which exhibits expression exclusively in testis and a broad range of human cancers. THOR knockdown and overexpression in multiple cell lines and animal models alters cell or tumor growth supporting an oncogenic role. We discovered a conserved interaction of THOR with IGF2BP1 and show that THOR contributes to the mRNA stabilization activities of IGF2BP1. Notably, transgenic THOR knockout produced fertilization defects in zebrafish and also conferred a resistance to melanoma onset. Likewise, ectopic expression of human THOR in zebrafish accelerated the onset of melanoma. THOR represents a novel class of functionally important cancer/testis lncRNAs whose structure and function have undergone positive evolutionary selection.

Exploring LIPIDs for their potential to improves bioavailability of lipophilic drugs candidates: A review.

This review aims to provide a thorough examination of the benefits, challenges, and advancements in utilizing lipids for more effective drug delivery, ultimately contributing to the development of innovative approaches in pharmaceutical science. Lipophilic drugs, characterized by low aqueous solubility, present a formidable challenge in achieving effective delivery and absorption within the human body. To address this issue, one promising approach involves harnessing the potential of lipids. Lipids, in their diverse forms, serve as carriers, leveraging their unique capacity to enhance solubility, stability, and absorption of these challenging drugs. By facilitating improved intestinal solubility and selective lymphatic absorption of porously permeable drugs, lipids offer an array of possibilities for drug delivery. This versatile characteristic not only bolsters the pharmacological efficacy of drugs with low bioavailability but also contributes to enhanced therapeutic performance, ultimately reducing the required dose size and associated costs. This comprehensive review delves into the strategic formulation approaches that employ lipids as carriers to ameliorate drug solubility and bioavailability. Emphasis is placed on the critical considerations of lipid type, composition, and processing techniques when designing lipid-based formulations. This review meticulously examines the multifaceted challenges that come hand in hand with lipid-based formulations for lipophilic drugs, offering an insightful perspective on future trends. Regulatory considerations and the broad spectrum of potential applications are also thoughtfully discussed. In summary, this review presents a valuable repository of insights into the effective utilization of lipids as carriers, all aimed at elevating the bioavailability of lipophilic drugs.

Pathogenesis and management of traumatic brain injury (TBI): role of neuroinflammation and anti-inflammatory drugs.

Traumatic brain injury (TBI) is an important global health concern that represents a leading cause of death and disability. It occurs due to direct impact or hit on the head caused by factors such as motor vehicles, crushes, and assaults. During the past decade, an abundance of new evidence highlighted the importance of inflammation in the secondary damage response that contributes to neurodegenerative and neurological deficits after TBI. It results in disruption of the blood-brain barrier (BBB) and initiates the release of macrophages, neutrophils, and lymphocytes at the injury site. A growing number of researchers have discovered various signalling pathways associated with the initiation and progression of inflammation. Targeting different signalling pathways (NF-κB, JAK/STAT, MAPKs, PI3K/Akt/mTOR, GSK-3, Nrf2, RhoGTPase, TGF-ß1, and NLRP3) helps in the development of novel anti-inflammatory drugs in the management of TBI. Several synthetic and herbal drugs with both anti-inflammatory and neuroprotective potential showed effective results. This review summarizes different signalling pathways, associated pathologies, inflammatory mediators, pharmacological potential, current status, and challenges with anti-inflammatory drugs.

Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer.

Men who develop metastatic castration-resistant prostate cancer (CRPC) invariably succumb to the disease. Progression to CRPC after androgen ablation therapy is predominantly driven by deregulated androgen receptor (AR) signalling. Despite the success of recently approved therapies targeting AR signalling, such as abiraterone and second-generation anti-androgens including MDV3100 (also known as enzalutamide), durable responses are limited, presumably owing to acquired resistance. Recently, JQ1 and I-BET762 two selective small-molecule inhibitors that target the amino-terminal bromodomains of BRD4, have been shown to exhibit anti-proliferative effects in a range of malignancies. Here we show that AR-signalling-competent human CRPC cell lines are preferentially sensitive to bromodomain and extraterminal (BET) inhibition. BRD4 physically interacts with the N-terminal domain of AR and can be disrupted by JQ1 (refs 11, 13). Like the direct AR antagonist MDV3100, JQ1 disrupted AR recruitment to target gene loci. By contrast with MDV3100, JQ1 functions downstream of AR, and more potently abrogated BRD4 localization to AR target loci and AR-mediated gene transcription, including induction of the TMPRSS2-ERG gene fusion and its oncogenic activity. In vivo, BET bromodomain inhibition was more efficacious than direct AR antagonism in CRPC xenograft mouse models. Taken together, these studies provide a novel epigenetic approach for the concerted blockade of oncogenic drivers in advanced prostate cancer.

Immune associated LncRNAs identify novel prognostic subtypes of renal clear cell carcinoma.

Kidney Renal Clear Cell Carcinoma (KIRC) is a significant cause of cancer-related deaths. Here, we aim to identify the LncRNAs associated with the immune system and characterise their clinical utility in KIRC. A total of 504 patients' data was used from TCGA-GDC. In silico correlation analysis identified 143 LncRNAs associated with immune-related genes (r > 0.7, P < 0.05). K-means consensus method clustered KIRC samples in three immune clusters, namely cluster C1, C2, and C3 based on the expression of 143 immune-related LncRNAs. Kaplan-Meier analysis showed that C3 patients survived significantly worse than the other two clusters (P < 0.0001). A comparison of TCGA miRNA, mRNA cluster with immune cluster showed the independence and robustness of immune clusters (HR = 2.02 and P = 2.12 × 10-8 ). The GSEA and CIBERSORT analysis showed high enrichment of poorly activated T-cells in C3 patients. To define LncRNA immune prognostic signature, we randomly divided the TCGA sample into discovery and validation sets. By utilising multivariate Cox regression analysis, we identified and validated a seven LncRNA immune prognostic signature score (LIPS score) (HR = 1.43 and P = 2.73 × 10-6 ) in KIRC. Comparison of LIPS score with all the clinical factors validated its independence and superiority in KIRC prognosis. In summary, we identified LncRNAs associated with the immune system and showed the presence of prognostic subtypes of KIRC patients based on immune-related LncRNA expression. We also identified a novel immune LncRNA based gene-signature for KIRC patients' prognostication.

MechRNA: prediction of lncRNA mechanisms from RNA-RNA and RNA-protein interactions.

Motivation: Long non-coding RNAs (lncRNAs) are defined as transcripts longer than 200 nt that do not get translated into proteins. Often these transcripts are processed (spliced, capped and polyadenylated) and some are known to have important biological functions. However, most lncRNAs have unknown or poorly understood functions. Nevertheless, because of their potential role in cancer, lncRNAs are receiving a lot of attention, and the need for computational tools to predict their possible mechanisms of action is more than ever. Fundamentally, most of the known lncRNA mechanisms involve RNA-RNA and/or RNA-protein interactions. Through accurate predictions of each kind of interaction and integration of these predictions, it is possible to elucidate potential mechanisms for a given lncRNA. Results: Here, we introduce MechRNA, a pipeline for corroborating RNA-RNA interaction prediction and protein binding prediction for identifying possible lncRNA mechanisms involving specific targets or on a transcriptome-wide scale. The first stage uses a version of IntaRNA2 with added functionality for efficient prediction of RNA-RNA interactions with very long input sequences, allowing for large-scale analysis of lncRNA interactions with little or no loss of optimality. The second stage integrates protein binding information pre-computed by GraphProt, for both the lncRNA and the target. The final stage involves inferring the most likely mechanism for each lncRNA/target pair. This is achieved by generating candidate mechanisms from the predicted interactions, the relative locations of these interactions and correlation data, followed by selection of the most likely mechanistic explanation using a combined P-value. We applied MechRNA on a number of recently identified cancer-related lncRNAs (PCAT1, PCAT29 and ARLnc1) and also on two well-studied lncRNAs (PCA3 and 7SL). This led to the identification of hundreds of high confidence potential targets for each lncRNA and corresponding mechanisms. These predictions include the known competitive mechanism of 7SL with HuR for binding on the tumor suppressor TP53, as well as mechanisms expanding what is known about PCAT1 and ARLn1 and their targets BRCA2 and AR, respectively. For PCAT1-BRCA2, the mechanism involves competitive binding with HuR, which we confirmed using HuR immunoprecipitation assays. Availability and implementation: MechRNA is available for download at https://bitbucket.org/compbio/mechrna. Supplementary information: Supplementary data are available at Bioinformatics online.

The landscape of antisense gene expression in human cancers.

High-throughput RNA sequencing has revealed more pervasive transcription of the human genome than previously anticipated. However, the extent of natural antisense transcripts' (NATs) expression, their regulation of cognate sense genes, and the role of NATs in cancer remain poorly understood. Here, we use strand-specific paired-end RNA sequencing (ssRNA-seq) data from 376 cancer samples covering nine tissue types to comprehensively characterize the landscape of antisense expression. We found consistent antisense expression in at least 38% of annotated transcripts, which in general is positively correlated with sense gene expression. Investigation of sense/antisense pair expressions across tissue types revealed lineage-specific, ubiquitous and cancer-specific antisense loci transcription. Comparisons between tumor and normal samples identified both concordant (same direction) and discordant (opposite direction) sense/antisense expression patterns. Finally, we provide OncoNAT, a catalog of cancer-related genes with significant antisense transcription, which will enable future investigations of sense/antisense regulation in cancer. Using OncoNAT we identified several functional NATs, including NKX2-1-AS1 that regulates the NKX2-1 oncogene and cell proliferation in lung cancer cells. Overall, this study provides a comprehensive account of NATs and supports a role for NATs' regulation of tumor suppressors and oncogenes in cancer biology.

Parametric coherent receiver.

We present the parametric coherent receiver based on a two-mode pump-degenerate fiber optical parametric amplifier (FOPA). The receiver is inherently single-ended and offers a simultaneous gain and coherent mixing of the received signal and a reference wave (known as a local oscillator signal) with, in principle, arbitrary wavelength separation. We analyze the receiver theoretically and in a proof-of-concept experiment. As a reference we compare the performance to a standard single-ended homodyne coherent receiver.

Quadrature demultiplexing using a degenerate vector parametric amplifier.

We report on quadrature demultiplexing of a quadrature phase-shift keying (QPSK) signal into two cross-polarized binary phase-shift keying (BPSK) signals with negligible penalty at bit-error rate (BER) equal to 10(-9). The all-optical quadrature demultiplexing is achieved using a degenerate vector parametric amplifier operating in phase-insensitive mode. We also propose and demonstrate the use of a novel and simple phase-locked loop (PLL) scheme based on detecting the envelope of one of the signals after demultiplexing in order to achieve stable quadrature decomposition.

Antioxidative and neuroprotective potential of Acorus calamus linn. and Cordia dichotoma G. Forst. In Alzheimer's type dementia in rodent.

The goal of this research study was to see how plant extracts of Acorus calamus Linn. and Cordia dichotoma G. Forst. overcome scopolamine-induced Alzheimer's type dementia in mice by activating the cholinergic system, anti-oxidant and protection of neuronal death in the brain (hippocampus region). Scopolamine (1 mg/kg i.p.) reduced mice's routine in behavioral parameters such as Morris Water Maze (MWM), Elevated Plus Maze (EPM), and also the locomotor activity. It also decreases antioxidant levels such as Reduced glutathione (GSH) and also Superoxide dismutase (SOD) but also increases the level of Acetylcholinesterase enzyme (AChE) in brain. Assessment of various behavioral, and biochemical parameters (AChE, SOD, GSH, and Nitrite level) were compared with each group. Acorus calamus (hydro-alcoholic 1:1) 600 mg/kg p.o. and the combination (Acorus calamus 600 mg/kg p.o. + Cordia dichotoma 750 mg/kg p.o.) group showed significant results as compared to Cordia dichotoma 750 mg/kg p.o.in behavioral as well as in biochemical parameters. Histological studies showed significant neuroprotection in the Acorus calamus-treated group and the combination-treated groups. In the future, the Acorus calamus and the combination are possibly helpful in the treatment of various cognitive disorders or it may be valuable to investigate the pharmacological potential of such plant extracts during the treatment of neurodegenerative disorders.

Lipid Horizons: Recent Advances and Future Prospects in LBDDS for Oral Administration of Antihypertensive Agents.

The lipid-based drug delivery system (LBDDS) is a well-established technique that is anticipated to bring about comprehensive transformations in the pharmaceutical field, impacting the management and administration of drugs, as well as treatment and diagnosis. Various LBDDSs verified to be an efficacious mechanism for monitoring hypertension systems are SEDDS (self-nano emulsifying drug delivery), nanoemulsion, microemulsions, vesicular systems (transferosomes and liposomes), and solid lipid nanoparticles. LBDDSs overcome the shortcomings that are associated with antihypertensive agents because around fifty percent of the antihypertensive agents experience a few drawbacks including short half-life because of hepatic first-pass metabolism, poor aqueous solubility, low permeation rate, and undesirable side effects. This review emphasizes antihypertensive agents that were encapsulated into the lipid carrier to improve their poor oral bioavailability. Incorporating cutting-edge technologies such as nanotechnology and targeted drug delivery, LBDDS holds promise in addressing the multifactorial nature of hypertension. By fine-tuning drug release profiles and enhancing drug uptake at specific sites, LBDDS can potentially target renin-angiotensin-aldosterone system components, sympathetic nervous system pathways, and endothelial dysfunction, all of which play crucial roles in hypertension pathophysiology. The future of hypertension management using LBDDS is promising, with ongoing reviews focusing on precision medicine approaches, improved biocompatibility, and reduced toxicity. As we delve deeper into understanding the intricate mechanisms underlying hypertension, LBDDS offers a pathway to develop next-generation antihypertensive therapies that are safer, more effective, and tailored to individual patient needs.

Phytoimmunomodulators: A review of natural modulators for complex immune system.

In the past few decades, the medicinal properties of plants and their effects on the human immune system are being studied extensively. Plants are an incredible source of traditional medicines that help cure various diseases, including altered immune mechanisms and are economical and benign compared to allopathic medicines. Reported data in written documents such as Traditional Chinese medicine, Indian Ayurvedic medicine support the supplementation of botanicals for immune defense reactions in the body and can lead to safe and effective immunity responses. Additionally, some botanicals are well-identified as magical herbal remedies because they act upon the pathogen directly and help boost the immunity of the host. Chemical compounds, also known as phytochemicals, obtained from these botanicals looked promising due to their effects on the human immune system by modulating the lymphocytes which subsequently reduce the chances of getting infected. This paper summarises most documented phytochemicals and how they act on the immune system, their properties and possible mechanisms, screening conventions, formulation guidelines, comparison with synthetic immunity-enhancers, marketed immunity-boosting products, and immune-booster role in the ongoing ghastly corona virus wave. However, it focuses mainly on plant metabolites as immunomodulators. In addition, it also sheds light on the current advancements and future possibilities in this field. From this thorough study, it can be stated that the plant-based secondary metabolites contribute significantly to immunity building and could prove to be valuable medicaments for the design and development of novel immunomodulators even for a pandemic like COVID-19.

Novel roles for the E3 ubiquitin ligase atrophin-interacting protein 4 and signal transduction adaptor molecule 1 in G protein-coupled receptor signaling.

The CXCL12/CXCR4 signaling axis plays an important role in human health and disease; however, the molecular mechanisms mediating CXCR4 signaling remain poorly understood. Ubiquitin modification of CXCR4 by the E3 ubiquitin ligase AIP4 is required for lysosomal sorting and degradation, which is mediated by the endosomal sorting complex required for transport (ESCRT) machinery. CXCR4 sorting is regulated by an interaction between endosomal localized arrestin-2 and STAM-1, an ESCRT-0 component. Here, we report a novel role for AIP4 and STAM-1 in regulation of CXCR4 signaling that is distinct from their function in CXCR4 trafficking. Depletion of AIP4 and STAM-1 by siRNA caused significant inhibition of CXCR4-induced ERK-1/2 activation, whereas overexpression of these proteins enhanced CXCR4 signaling. We further show that AIP4 and STAM-1 physically interact and that the proline-rich region in AIP4 and the SH3 domain in STAM-1 are essential for the interaction. Overexpression of an AIP4 catalytically inactive mutant and a mutant that shows poor binding to STAM-1 fails to enhance CXCR4-induced ERK-1/2 signaling, as compared with wild-type AIP4, suggesting that the interaction between AIP4 and STAM-1 and the ligase activity of AIP4 are essential for ERK-1/2 activation. Remarkably, a discrete subpopulation of AIP4 and STAM-1 resides in caveolar microdomains with CXCR4 and appears to mediate ERK-1/2 signaling. We propose that AIP4-mediated ubiquitination of STAM-1 in caveolae coordinates activation of ERK-1/2 signaling. Thus, our study reveals a novel function for ubiquitin in the regulation of CXCR4 signaling, which may be broadly applicable to other G protein-coupled receptors.

Nanoemulsion: An Emerging Novel Technology for Improving the Bioavailability of Drugs.

The pharmaceutical sector has made considerable strides recently, emphasizing improving drug delivery methods to increase the bioavailability of various drugs. When used as a medication delivery method, nanoemulsions have multiple benefits. Their small droplet size, which is generally between 20 and 200 nanometers, creates a significant interfacial area for drug dissolution, improving the solubility and bioavailability of drugs that are weakly water-soluble. Additionally, nanoemulsions are a flexible platform for drug administration across various therapeutic areas since they can encapsulate hydrophilic and hydrophobic medicines. Nanoemulsion can be formulated in multiple dosage forms, for example, gels, creams, foams, aerosols, and sprays by using low-cost standard operative processes and also be taken orally, topically, topically, intravenously, intrapulmonary, intranasally, and intraocularly. The article explores nanoemulsion formulation and production methods, emphasizing the role of surfactants and cosurfactants in creating stable formulations. In order to customize nanoemulsions to particular medication delivery requirements, the choice of components and production techniques is crucial in assuring the stability and efficacy of the finished product. Nanoemulsions are a cutting-edge technology with a lot of potential for improving medication bioavailability in a variety of therapeutic contexts. They are a useful tool in the creation of innovative pharmaceutical formulations due to their capacity to enhance drug solubility, stability, and delivery. Nanoemulsions are positioned to play a crucial role in boosting medication delivery and enhancing patient outcomes as this field of study continues to advance.

Small ubiquitin-like modifier modification of arrestin-3 regulates receptor trafficking.

Nonvisual arrestins are regulated by direct post-translational modifications, such as phosphorylation, ubiquitination, and nitrosylation. However, whether arrestins are regulated by other post-translational modifications remains unknown. Here we show that nonvisual arrestins are modified by small ubiquitin-like modifier 1 (SUMO-1) upon activation of ß(2)-adrenergic receptor (ß(2)AR). Lysine residues 295 and 400 in arrestin-3 fall within canonical SUMO consensus sites, and mutagenic analysis reveals that Lys-400 represents the main SUMOylation site. Depletion of the SUMO E2 modifying enzyme Ubc9 blocks arrestin-3 SUMOylation and attenuates ß(2)AR internalization, suggesting that arrestin SUMOylation mediates G protein-coupled receptor endocytosis. Consistent with this, expression of a SUMO-deficient arrestin mutant failed to promote ß(2)AR internalization as compared with wild-type arrestin-3. Our data reveal an unprecedented role for SUMOylation in mediating GPCR endocytosis and provide novel mechanistic insight into arrestin function and regulation.

Overview of therapeutic targets in management of dementia.

Dementia is defined as a gradual cognitive impairment that interferes with everyday tasks, and is a leading cause of dependency, disability, and mortality. According to the current scenario, millions of individuals worldwide have dementia. This review provides with an overview of dementia before moving on to its subtypes (neurodegenerative and non-neurodegenerative) and pathophysiology. It also discusses the incidence and severity of dementia, focusing on Alzheimer's disease with its different hypotheses such as Aß cascade hypothesis, Tau hypothesis, inflammatory hypothesis, cholinergic and oxidative stress hypothesis. Alzheimer's disease is the most common type and a progressive neurodegenerative illness distinct by neuronal loss and resulting cognitive impairment, leading to dementia. Alzheimer's disease (AD) is considered the most familiar neurodegenerative dementias that affect mostly older population. There are still no disease-modifying therapies available for any dementias at this time, but there are various methods for lowering the risk to dementia patients by using suitable diagnostic and evaluation methods. Thereafter, the management and treatment of primary risk elements of dementia are reviewed. Finally, the future perspectives of dementia (AD) focusing on the impact of the new treatment are discussed.

Geminin overexpression prevents the completion of topoisomerase IIα chromosome decatenation, leading to aneuploidy in human mammary epithelial cells.

INTRODUCTION: The nuclear enzyme topoisomerase IIα (TopoIIα) is able to cleave DNA in a reversible manner, making it a valuable target for agents such as etoposide that trap the enzyme in a covalent bond with the 5' DNA end to which it cleaves. This prevents DNA religation and triggers cell death in cancer cells. However, development of resistance to these agents limits their therapeutic use. In this study, we examined the therapeutic targeting of geminin for improving the therapeutic potential of TopoIIα agents. METHODS: Human mammary epithelial (HME) cells and several breast cancer cell lines were used in this study. Geminin, TopoIIα and cell division cycle 7 (Cdc7) silencing were done using specific small interfering RNA. Transit or stable inducible overexpression of these proteins and casein kinase Iε (CKIε) were also used, as well as several pharmacological inhibitors that target TopoIIα, Cdc7 or CKIε. We manipulated HME cells that expressed H2B-GFP, or did not, to detect chromosome bridges. Immunoprecipitation and direct Western blot analysis were used to detect interactions between these proteins and their total expression, respectively, whereas interactions on chromosomal arms were detected using a trapped in agarose DNA immunostaining assay. TopoIIα phosphorylation by Cdc7 or CKIε was done using an in vitro kinase assay. The TopoGen decatenation kit was used to measure TopoIIα decatenation activity. Finally, a comet assay and metaphase chromosome spread were used to detect chromosome breakage and changes in chromosome condensation or numbers, respectively. RESULTS: We found that geminin and TopoIIα interact primarily in G2/M/early G1 cells on chromosomes, that geminin recruits TopoIIα to chromosomal decatenation sites or vice versa and that geminin silencing in HME cells triggers the formation of chromosome bridges by suppressing TopoIIα access to chromosomal arms. CKIε kinase phosphorylates and positively regulates TopoIIα chromosome localization and function. CKIε kinase overexpression or Cdc7 kinase silencing, which we show phosphorylates TopoIIα in vitro, restored DNA decatenation and chromosome segregation in geminin-silenced cells before triggering cell death. In vivo, at normal concentration, geminin recruits the deSUMOylating sentrin-specific proteases SENP1 and SENP2 enzymes to deSUMOylate chromosome-bound TopoIIα and promote its release from chromosomes following completion of DNA decatenation. In cells overexpressing geminin, premature departure of TopoIIα from chromosomes is thought to be due to the fact that geminin recruits more of these deSUMOylating enzymes, or recruits them earlier, to bound TopoIIα. This triggers premature release of TopoIIα from chromosomes, which we propose induces aneuploidy in HME cells, since chromosome breakage generated through this mechanism were not sensed and/or repaired and the cell cycle was not arrested. Expression of mitosis-inducing proteins such as cyclin A and cell division kinase 1 was also increased in these cells because of the overexpression of geminin. CONCLUSIONS: TopoIIα recruitment and its chromosome decatenation function require a normal level of geminin. Geminin silencing induces a cytokinetic checkpoint in which Cdc7 phosphorylates TopoIIα and inhibits its chromosomal recruitment and decatenation and/or segregation function. Geminin overexpression prematurely deSUMOylates TopoIIα, triggering its premature departure from chromosomes and leading to chromosomal abnormalities and the formation of aneuploid, drug-resistant cancer cells. On the basis of our findings, we propose that therapeutic targeting of geminin is essential for improving the therapeutic potential of TopoIIα agents.

Functional and Mechanistic Interrogation of BET Bromodomain Degraders for the Treatment of Metastatic Castration-resistant Prostate Cancer.

PURPOSE: The bromodomain and extraterminal (BET)-containing proteins (BRD2/3/4) are essential epigenetic coregulators for prostate cancer growth. BRD inhibitors have shown promise for treatment of metastatic castration-resistant prostate cancer (mCRPC), and have been shown to function even in the context of resistance to next-generation AR-targeted therapies such as enzalutamide and abiraterone. Their clinical translation, however, has been limited by off-target effects, toxicity, and rapid resistance. EXPERIMENTAL DESIGN: We have developed a series of molecules that target BET bromodomain proteins through their proteasomal degradation, improving efficacy and specificity of standard inhibitors. We tested their efficacy by utilizing prostate cancer cell lines and patient-derived xenografts, as well as several techniques including RNA-sequencing, mass spectroscopic proteomics, and lipidomics. RESULTS: BET degraders function in vitro and in vivo to suppress prostate cancer growth. These drugs preferentially affect AR-positive prostate cancer cells (22Rv1, LNCaP, VCaP) over AR-negative cells (PC3 and DU145), and proteomic and genomic mechanistic studies confirm disruption of oncogenic AR and MYC signaling at lower concentrations than BET inhibitors. We also identified increases in polyunsaturated fatty acids (PUFA) and thioredoxin-interacting protein (TXNIP) as potential pharmacodynamics biomarkers for targeting BET proteins. CONCLUSIONS: Compounds inducing the pharmacologic degradation of BET proteins effectively target the major oncogenic drivers of prostate cancer, and ultimately present a potential advance in the treatment of mCRPC. In particular, our compound dBET-3, is most suited for further clinical development.

Characterizing the Therapeutic Potential of a Potent BET Degrader in Merkel Cell Carcinoma.

Studies on the efficacy of small molecule inhibitors in Merkel cell carcinoma (MCC) have been limited and largely inconclusive. In this study, we investigated the therapeutic potential of a potent BET degrader, BETd-246, in the treatment of MCC. We found that MCC cell lines were significantly more sensitive to BETd-246 than to BET inhibitor treatment. Therapeutic targeting of BET proteins resulted in a loss of "MCC signature" genes but not MYC expression as previously described irrespective of Merkel cell polyomavirus (MCPyV) status. In MCPyV+ MCC cells, BETd-246 alone suppressed downstream targets in the MCPyV-LT Ag axis. We also found enrichment of HOX and cell cycle genes in MCPyV- MCC cell lines that were intrinsically resistant to BETd-246. Our findings uncover a requirement for BET proteins in maintaining MCC lineage identity and point to the potential utility of BET degraders for treating MCC.