Rational optimization of a transcription factor activation domain inhibitor.

Transcription factors are among the most attractive therapeutic targets but are considered largely 'undruggable' in part due to the intrinsically disordered nature of their activation domains. Here we show that the aromatic character of the activation domain of the androgen receptor, a therapeutic target for castration-resistant prostate cancer, is key for its activity as transcription factor, allowing it to translocate to the nucleus and partition into transcriptional condensates upon activation by androgens. On the basis of our understanding of the interactions stabilizing such condensates and of the structure that the domain adopts upon condensation, we optimized the structure of a small-molecule inhibitor previously identified by phenotypic screening.

Differential Gene Expression Profiles between N-Terminal Domain and Ligand-Binding Domain Inhibitors of Androgen Receptor Reveal Ralaniten Induction of Metallothionein by a Mechanism Dependent on MTF1.

Hormonal therapies for prostate cancer target the androgen receptor (AR) ligand-binding domain (LBD). Clinical development for inhibitors that bind to the N-terminal domain (NTD) of AR has yielded ralaniten and its analogues. Ralaniten acetate is well tolerated in patients at 3600 mgs/day.

Pin1 inhibition improves the efficacy of ralaniten compounds that bind to the N-terminal domain of androgen receptor.

Therapies for lethal castration-resistant prostate cancer (CRPC) are an unmet medical need. One mechanism underlying CRPC and resistance to hormonal therapies is the expression of constitutively active splice variant(s) of androgen receptor (AR-Vs) that lack its C-terminus ligand-binding domain. Transcriptional activities of AR-Vs and full-length AR reside in its N-terminal domain (NTD).

Structure-Activity Relationships for the Marine Natural Product Sintokamides: Androgen Receptor N-Terminus Antagonists of Interest for Treatment of Metastatic Castration-Resistant Prostate Cancer.

Synthetic analogues of the marine natural product sintokamides have been prepared in order to investigate the structure-activity relationships for the androgen receptor N-terminal domain (AR NTD) antagonist activity of the sintokamide scaffold. An LNCaP cell-based transcriptional activity assay with an androgen-driven luciferase (Luc) reporter was used to monitor the potency of analogues. The data have shown that the chlorine atoms on the leucine side chains are essential for potent activity.

Ralaniten Sensitizes Enzalutamide-Resistant Prostate Cancer to Ionizing Radiation in Prostate Cancer Cells that Express Androgen Receptor Splice Variants.

Blocking androgen receptor (AR) transcriptional activity by androgen deprivation therapy (ADT) improves the response to radiotherapy for intermediate and high risk prostate cancer. Unfortunately, ADT, antiandrogens, and abiraterone increase expression of constitutively active splice variants of AR (AR-Vs) which regulate DNA damage repair leading to resistance to radiotherapy. Here we investigate whether blocking the transcriptional activities of full-length AR and AR-Vs with ralaniten leads to enhanced sensitivity to radiotherapy.

Revealing Metabolic Liabilities of Ralaniten To Enhance Novel Androgen Receptor Targeted Therapies.

Inhibition of the androgen receptor (AR) is the mainstay treatment for advanced prostate cancer. Ralaniten (formally EPI-002) prevents AR transcriptional activity by binding to its N-terminal domain (NTD) which is essential for transcriptional activity. Ralaniten acetate (EPI-506) the triacetate pro-drug of ralaniten, remains the only AR-NTD inhibitor to have entered clinical trials (NCT02606123).

Inhibition of androgen receptor by decoy molecules delays progression to castration-recurrent prostate cancer.

Androgen receptor (AR) is a member of the steroid receptor family and a therapeutic target for all stages of prostate cancer. AR is activated by ligand binding within its C-terminus ligand-binding domain (LBD). Here we show that overexpression of the AR NTD to generate decoy molecules inhibited both the growth and progression of prostate cancer in castrated hosts.

Sintokamide A Is a Novel Antagonist of Androgen Receptor That Uniquely Binds Activation Function-1 in Its Amino-terminal Domain.

Androgen receptor (AR) is a validated drug target for all stages of prostate cancer including metastatic castration-resistant prostate cancer (CRPC). All current hormone therapies for CRPC target the C-terminal ligand-binding domain of AR and ultimately all fail with resumed AR transcriptional activity. Within the AR N-terminal domain (NTD) is activation function-1 (AF-1) that is essential for AR transcriptional activity.

An imaging agent to detect androgen receptor and its active splice variants in prostate cancer.

Constitutively active splice variants of androgen receptor (AR-Vs) lacking ligand-binding domain (LBD) are a mechanism of resistance to androgen receptor LBD-targeted (AR LBD-targeted) therapies for metastatic castration-resistant prostate cancer (CRPC). There is a strong unmet clinical need to identify prostate cancer patients with AR-V-positive lesions to determine whether they will benefit from further AR LBD-targeting therapies or should receive taxanes or investigational drugs like EPI-506 or galeterone. Both EPI-506 (NCT02606123) and galeterone (NCT02438007) are in clinical trials and are proposed to have efficacy against lesions that are positive for AR-Vs.

Targeting Androgen Receptor Activation Function-1 with EPI to Overcome Resistance Mechanisms in Castration-Resistant Prostate Cancer.

Purpose: Persistent androgen receptor (AR) transcriptional activity is clinically evident in castration-resistant prostate cancer (CRPC). Therefore, AR remains as a viable therapeutic target for CRPC. All current hormonal therapies target the C-terminus ligand-binding domain (LBD) of AR.

Cotargeting Androgen Receptor Splice Variants and mTOR Signaling Pathway for the Treatment of Castration-Resistant Prostate Cancer.

Purpose: The PI3K/Akt/mTOR pathway is activated in most castration-resistant prostate cancers (CRPC). Transcriptionally active androgen receptor (AR) plays a role in the majority of CRPCs. Therefore, cotargeting full-length (FL) AR and PI3K/Akt/mTOR signaling has been proposed as a possible, more effective therapeutic approach for CRPC.

High Hydrostatic Pressure Pretreatment of Whey Protein Isolates Improves Their Digestibility and Antioxidant Capacity.

Whey proteins have well-established antioxidant and anti-inflammatory bioactivities. High hydrostatic pressure processing of whey protein isolates increases their digestibility resulting in enhanced antioxidant and anti-inflammatory effects. This study compared the effects of different digestion protocols on the digestibility of pressurized (pWPI) and native (nWPI) whey protein isolates and the antioxidant and anti-inflammatory properties of the hydrolysates.

Factors affecting discharge destination following lung transplantation.

Background: Lung transplant (LT) recipients requiring additional care may be referred to inpatient rehabilitation prior to discharge home. This study seeks to describe discharge destinations following LT, compare the characteristics of patients discharged to different destinations, and identify the predictors of discharge destination.

Methods: Retrospective study of 243 LT recipients who survived to hospital discharge between 2006 and 2009.

Characterization of niphatenones that inhibit androgen receptor N-terminal domain.

Androgen ablation therapy causes a temporary reduction in tumor burden in patients with advanced prostate cancer. Unfortunately the malignancy will return to form lethal castration-recurrent prostate cancer (CRPC). The androgen receptor (AR) remains transcriptionally active in CRPC in spite of castrate levels of androgens in the blood.

Bladder base tenderness in the etiology of deep dyspareunia.

Introduction: Bladder base tenderness can be present on pelvic exam in women with pelvic pain. However, its exact prevalence and clinical implications are not well understood.

Aim: The aim of this study was to determine whether bladder base tenderness is associated with specific symptoms or signs in women, particularly dyspareunia.

Fundus autofluorescence imaging: Fundamentals and clinical relevance.

Fundus autofluorescence (FAF), a relatively new imaging modality, focuses on the fluorescent properties of pigments in the retina to generate images that help us view various disease processes from a different perspective. It aids us in the understanding of the pathophysiology of different retinal disorders. Recently, FAF imaging is being used commonly to help us in the diagnosis, prognosis as well as in determining the treatment response of various retinal disorders.

An androgen receptor N-terminal domain antagonist for treating prostate cancer.

Hormone therapies for advanced prostate cancer target the androgen receptor (AR) ligand-binding domain (LBD), but these ultimately fail and the disease progresses to lethal castration-resistant prostate cancer (CRPC). The mechanisms that drive CRPC are incompletely understood, but may involve constitutively active AR splice variants that lack the LBD. The AR N-terminal domain (NTD) is essential for AR activity, but targeting this domain with small-molecule inhibitors is complicated by its intrinsic disorder.

Spongian diterpenoids inhibit androgen receptor activity.

Androgen receptor is a ligand-activated transcription factor and a validated drug target for all stages of prostate cancer. Antiandrogens compete with physiologic ligands for androgen receptor ligand-binding domain (LBD). High-throughput screening of a marine natural product library for small molecules that inhibit androgen receptor transcriptional activity yielded the furanoditerpenoid spongia-13(16),-14-dien-19-oic acid, designated terpene 1 (T1).

Whey protein hydrolysates decrease IL-8 secretion in lipopolysaccharide (LPS)-stimulated respiratory epithelial cells by affecting LPS binding to Toll-like receptor 4.

Unlabelled: Whey proteins (WP) exert anti-inflammatory and antioxidant effects. Hyperbaric pressurisation of whey increases its digestibility and changes the spectrum of peptides released during digestion. We have shown that dietary supplementation with pressurised whey improves nutritional status and systemic inflammation in patients with cystic fibrosis (CF).

Niphatenones, glycerol ethers from the sponge Niphates digitalis block androgen receptor transcriptional activity in prostate cancer cells: structure elucidation, synthesis, and biological activity.

Extracts of the marine sponge Niphates digitalis collected in Dominica showed strong activity in a cell-based assay designed to detect antagonists of the androgen receptor (AR) that could act as lead compounds for the development of a new class of drugs to treat castration recurrent prostate cancer (CRPC). Assay-guided fractionation showed that niphatenones A (3) and B (4), two new glycerol ether lipids, were the active components of the extracts. The structures of 3 and 4 were elucidated by analysis of NMR and MS data and confimed via total synthesis.

Down-regulation of cytokine-induced interleukin-8 requires inhibition of p38 mitogen-activated protein kinase (MAPK) via MAPK phosphatase 1-dependent and -independent mechanisms.

Down-regulation of overabundant interleukin (IL)-8 present in cystic fibrosis (CF) airways could ease excessive neutrophil burden and its deleterious consequences for the lung. IL-8 production in airway epithelial cells, stimulated with e.g.

Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor.

Castration-recurrent prostate cancer (CRPC) is suspected to depend on androgen receptor (AR). The AF-1 region in the amino-terminal domain (NTD) of AR contains most, if not all, of the transcriptional activity. Here we identify EPI-001, a small molecule that blocked transactivation of the NTD and was specific for inhibition of AR without attenuating transcriptional activities of related steroid receptors.

Sintokamides A to E, chlorinated peptides from the sponge Dysidea sp. that inhibit transactivation of the N-terminus of the androgen receptor in prostate cancer cells.

The new chlorinated peptides sintokamides A to E (1-5) have been isolated from specimens of the marine sponge Dysidea sp. collected in Indonesia. Their structures were elucidated by a combination of spectroscopic and single-crystal X-ray diffraction analyses.

Androgen receptor decoy molecules block the growth of prostate cancer.

The androgen receptor (AR) is activated by both ligand-dependent and -independent mechanisms. Current therapies for prostate cancer target the ligand-binding domain in the C terminus of the AR. However, ligand-independent activation of the AR occurs by the N-terminal domain (NTD), making the NTD a potential novel target for the treatment of hormone refractory prostate cancer.

Critical role of integrin-linked kinase in granule cell precursor proliferation and cerebellar development.

Integrin-linked kinase (ILK) is a serine/threonine protein kinase that plays an important role in integrin signaling and cell proliferation. We used Cre recombinase (Cre)-loxP technology to study CNS restricted knock-out of the ilk gene by either Nestin-driven or gfap-driven Cre-mediated recombination. Developmental changes in ilk-excised brain regions are similar to those observed in mice lacking the integrin beta1 subunit in the CNS, including defective laminin deposition, abnormal glial morphology, and alterations in granule cell migration.