Development of an orally bioavailable mSWI/SNF ATPase degrader and acquired mechanisms of resistance in prostate cancer.

Mammalian switch/sucrose nonfermentable (mSWI/SNF) ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic transcription factor chromatin accessibility. Here, we developed AU-24118, an orally bioavailable proteolysis-targeting chimera (PROTAC) degrader of mSWI/SNF ATPases (SMARCA2 and SMARCA4) and PBRM1. AU-24118 demonstrated tumor regression in a model of castration-resistant prostate cancer (CRPC) which was further enhanced with combination enzalutamide treatment, a standard of care androgen receptor (AR) antagonist used in CRPC patients.

Development of an orally bioavailable mSWI/SNF ATPase degrader and acquired mechanisms of resistance in prostate cancer.

Mammalian switch/sucrose non-fermentable (mSWI/SNF) ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic transcription factor chromatin accessibility. Here, we developed AU-24118, a first-in-class, orally bioavailable proteolysis targeting chimera (PROTAC) degrader of mSWI/SNF ATPases (SMARCA2 and SMARCA4) and PBRM1. AU-24118 demonstrated tumor regression in a model of castration-resistant prostate cancer (CRPC) which was further enhanced with combination enzalutamide treatment, a standard of care androgen receptor (AR) antagonist used in CRPC patients.

Differential Cellular Sensing of Fusion from within and Fusion from without during Virus Infection.

The physical entry of virus particles into cells triggers an innate immune response that is dependent on both calcium and nucleic acid sensors, with particles containing RNA or DNA genomes detected by RNA or DNA sensors, respectively. While membrane fusion in the absence of viral nucleic acid causes an innate immune response that is dependent on calcium, the involvement of nucleic acid sensors is poorly understood. Here, we used lipoplexes containing purified reovirus p14 fusion protein as a model of exogenous or fusion from without and a cell line expressing inducible p14 protein as a model of endogenous or fusion from within to examine cellular membrane fusion sensing events.

Manipulating the blood labyrinth barrier with mannitol to prevent cisplatin-induced hearing loss.

Cisplatin, a chemotherapeutic medication, remains in the cochlea indefinitely, causing permanent hearing loss. Mannitol, a diuretic medication, has been shown to increase the permeability of the blood labyrinth barrier (BLB). We hypothesize that mannitol increases the permeability of the BLB and therefore increases the rate of entry and egression of cisplatin and entry of otoprotective agents.

Magnetic Targeting of Gadolinium Contrast to Enhance MRI of the Inner Ear in Endolymphatic Hydrops.

Objectives: 1. Determine the feasibility and efficiency of local magnetic targeting delivery of gadolinium (Gad) contrast to the inner ear in rodents. 2.

Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer.

The switch/sucrose non-fermentable (SWI/SNF) complex has a crucial role in chromatin remodelling and is altered in over 20% of cancers. Here we developed a proteolysis-targeting chimera (PROTAC) degrader of the SWI/SNF ATPase subunits, SMARCA2 and SMARCA4, called AU-15330. Androgen receptor (AR) forkhead box A1 (FOXA1) prostate cancer cells are exquisitely sensitive to dual SMARCA2 and SMARCA4 degradation relative to normal and other cancer cell lines.

Design, synthesis, and biological evaluation of phenyl thiazole-based AR-V7 degraders.

Multiple Splice variants of AR have been reported in the past few years. These splice variants are upregulated in most cases of CRPC resulting in poor prognosis. Most of these variants lack the ligand binding domain (LBD) but still bind to DNA resulting in constitutive activation of downstream targets.

Retraction Notice To: Potential Health Benefits of Broccoli- A Chemico-Biological Overview.

The article "Potential health benefits of broccoli- a chemico-biological overview, published in Mini-Rev Med Chem 2009 Jun;9(6):749-59. By Hannah R. Vasanthi, Subhendu Mukherjee and Dipak K.

Local magnetic delivery of adeno-associated virus AAV2(quad Y-F)-mediated BDNF gene therapy restores hearing after noise injury.

Moderate noise exposure may cause acute loss of cochlear synapses without affecting the cochlear hair cells and hearing threshold; thus, it remains "hidden" to standard clinical tests. This cochlear synaptopathy is one of the main pathologies of noise-induced hearing loss (NIHL). There is no effective treatment for NIHL, mainly because of the lack of a proper drug-delivery technique.

Discovery of CA-4948, an Orally Bioavailable IRAK4 Inhibitor for Treatment of Hematologic Malignancies.

Small molecule potent IRAK4 inhibitors from a novel bicyclic heterocycle class were designed and synthesized based on hits identified from Aurigene's compound library. The advanced lead compound, CA-4948, demonstrated good cellular activity in ABC DLBCL and AML cell lines. Inhibition of TLR signaling leading to decreased IL-6 levels was also observed in whole blood assays.

Prostaglandin E inhibits profibrotic function of human pulmonary fibroblasts by disrupting Ca signaling.

We have shown that calcium (Ca) oscillations in human pulmonary fibroblasts (HPFs) contribute to profibrotic effects of transforming growth factor-β (TGF-β) and that disruption of these oscillations blunts features of pulmonary fibrosis. Prostaglandin E (PGE) exerts antifibrotic effects in the lung, but the mechanisms for this action are not well defined. We thus sought to explore interactions between PGE and the profibrotic agent TGF-β in pulmonary fibroblasts (PFs) isolated from patients with or without idiopathic pulmonary fibrosis (IPF).

Correction: Protective role of air potato (Dioscorea bulbifera) of yam family in myocardial ischemic reperfusion injury.

Correction for 'Protective role of air potato (Dioscorea bulbifera) of yam family in myocardial ischemic reperfusion injury' by Hannah Rachel Vasanthi et al., Food Funct., 2010, 1, 278-283.

ODM-203, a Selective Inhibitor of FGFR and VEGFR, Shows Strong Antitumor Activity, and Induces Antitumor Immunity.

Alterations in the gene encoding for the FGFR and upregulation of the VEGFR are found often in cancer, which correlate with disease progression and unfavorable survival. In addition, FGFR and VEGFR signaling synergistically promote tumor angiogenesis, and activation of FGFR signaling has been described as functional compensatory angiogenic signal following development of resistance to VEGFR inhibition. Several selective small-molecule FGFR kinase inhibitors are currently in clinical development.

TRPV4 Stimulation Releases ATP via Pannexin Channels in Human Pulmonary Fibroblasts.

We previously described several ionic conductances in human pulmonary fibroblasts, including one activated by two structurally distinct TRPV4 (transient receptor potential, vanilloid-type, subtype 4)-channel agonists: 4αPDD (4α-phorbol-12,13-didecanoate) and GSK1016790A. However, the TRPV4-activated current exhibited peculiar properties: it developed slowly over many minutes, exhibited reversal potentials that could vary by tens of millivolts even within a given cell, and was not easily reversed by subsequent addition of two distinct TRPV4-selective blockers (RN-1734 and HC-067047). In this study, we characterized that conductance more carefully.

Ca/calmodulin-dependent protein kinase IIβ and IIδ mediate TGFβ-induced transduction of fibronectin and collagen in human pulmonary fibroblasts.

It is now clear that in addition to activating several complex kinase pathways (Smad, MAP kinase, PI3 kinase), TGFβ also acts by elevating cytosolic Ca concentration within human pulmonary fibroblasts. Ca/calmodulin-dependent protein kinase II (CamK II) is also known to regulate gene expression in fibroblasts. In this study, we examined the interactions between calcium signaling, activation of CamK and other kinases, and extracellular matrix (ECM) gene expression.

Electrophysiological characterization of voltage-dependent calcium currents and TRPV4 currents in human pulmonary fibroblasts.

We have presented indirect evidence of a key role for voltage-dependent Ca(2+) currents in TGFβ-induced synthetic function in human pulmonary fibroblast (HPF), as well as in bleomycin-induced pulmonary fibrosis in mice. Others, however, have provided indirect evidence for transient receptor potential vanilloid 4 (TRPV4) channels in both of those effects. Unfortunately, definitive electrophysiological descriptions of both currents in HPFs have been entirely lacking.

Membrane Perturbation-Associated Ca2+ Signaling and Incoming Genome Sensing Are Required for the Host Response to Low-Level Enveloped Virus Particle Entry.

Unlabelled: The type I interferon (IFN) response is an important aspect of innate antiviral defense, and the transcription factor IRF3 plays an important role in its induction. Membrane perturbation during fusion, a necessary step for enveloped virus particle entry, appears sufficient to induce transcription of a subset of IFN-stimulated genes (ISGs) in an IRF3-dependent, IFN-independent fashion. IRF3 is emerging as a central node in host cell stress responses, although it remains unclear how different forms of stress activate IRF3.

Structure-guided discovery of 2-aryl/pyridin-2-yl-1H-indole derivatives as potent and selective hepsin inhibitors.

Hepsin, a type II transmembrane serine protease, is upregulated in prostate cancer and known to be involved in the progression of metastasis. Here we report a structure-guided approach, which resulted in the discovery of 2-aryl/pyridin-2-yl-1H-indole derivatives as potent and selective inhibitors of hepsin. Potent and selective inhibition of hepsin by compound 8 is likely due to interactions of the amidine group at the S1 site with the cyclohexyl ring from the 2-aryl group projecting towards the S1' site and the tert-hydroxyl group interacting with His57 side-chain as revealed by X-ray crystallography.

Calcium Homeostasis and Ionic Mechanisms in Pulmonary Fibroblasts.

Fibroblasts are key cellular mediators of many chronic interstitial lung diseases, including idiopathic pulmonary fibrosis, scleroderma, sarcoidosis, drug-induced interstitial lung disease, and interstitial lung disease in connective tissue disease. A great deal of effort has been expended to understand the signaling mechanisms underlying the various cellular functions of fibroblasts. Recently, it has been shown that Ca(2+) oscillations play a central role in the regulation of gene expression in human pulmonary fibroblasts.

Disruption of Calcium Signaling in Fibroblasts and Attenuation of Bleomycin-Induced Fibrosis by Nifedipine.

Fibrotic lung disease afflicts millions of people; the central problem is progressive lung destruction and remodeling. We have shown that external growth factors regulate fibroblast function not only through canonical signaling pathways but also through propagation of periodic oscillations in Ca(2+). In this study, we characterized the pharmacological sensitivity of the Ca(2+)oscillations and determined whether a blocker of those oscillations can prevent the progression of fibrosis in vivo.

Discovery of O-(3-carbamimidoylphenyl)-l-serine amides as matriptase inhibitors using a fragment-linking approach.

Matriptase is a cell-surface trypsin-like serine protease of epithelial origin, which cleaves and activates proteins including hepatocyte growth factor/scatter factor and proteases such as uPA, which are involved in the progression of various cancers. Here we report a fragment-linking approach, which led to the discovery of O-(3-carbamimidoylphenyl)-l-serine amides as potent matriptase inhibitors. The co-crystal structure of one of the potent inhibitors, 6 in complex with matriptase catalytic domain validated the working hypothesis guiding the development of this congeneric series and revealed the structural basis for matriptase inhibition.

Discovery of Pyridyl Bis(oxy)dibenzimidamide Derivatives as Selective Matriptase Inhibitors.

Matriptase belongs to trypsin-like serine proteases involved in matrix remodeling/degradation, growth regulation, survival, motility, and cell morphogenesis. Herein, we report a structure-based approach, which led to the discovery of sulfonamide and amide derivatives of pyridyl bis(oxy)benzamidine as potent and selective matriptase inhibitors. Co-crystal structures of selected compounds in complex with matriptase supported compound designing.

Structure-guided discovery of 1,3,5 tri-substituted benzenes as potent and selective matriptase inhibitors exhibiting in vivo antitumor efficacy.

Matriptase is a serine protease implicated in cancer invasion and metastasis. Expression of matriptase is frequently dysregulated in human cancers and matriptase has been reported to activate latent growth factors such as hepatocyte growth factor/scatter factor, and proteases such as urokinase plasminogen activator suggesting that matriptase inhibitors could have therapeutic potential in treatment of cancer. Here we report a structure-based approach which led to the discovery of selective and potent matriptase inhibitors with benzene as central core having 1,3,5 tri-substitution pattern.