Elucidating host cell response pathways and repurposing therapeutics for SARS-CoV-2 and other coronaviruses.

COVID-19, first reported in late 2019, is an ongoing pandemic that has been causing devastation across the globe. Although there are multiple vaccines that can prevent severe symptoms, effective COVID-19 therapeutics are still of importance. Using our proprietary in silico engine, we screened more than 22,000 unique compounds represented by over half a million gene expression profiles to uncover compounds that can be repurposed for SARS-CoV-2 and other coronaviruses in a timely and cost-efficient manner.

Restricted Delivery of Talazoparib Across the Blood-Brain Barrier Limits the Sensitizing Effects of PARP Inhibition on Temozolomide Therapy in Glioblastoma.

Poly ADP-ribose polymerase (PARP) inhibitors, including talazoparib, potentiate temozolomide efficacy in multiple tumor types; however, talazoparib-mediated sensitization has not been evaluated in orthotopic glioblastoma (GBM) models. This study evaluates talazoparib ± temozolomide in clinically relevant GBM models. Talazoparib at 1-3 nmol/L sensitized T98G, U251, and GBM12 cells to temozolomide, and enhanced DNA damage signaling and G-M arrest cyclical therapy with talazoparib (0.

Discovery of pyrazolopyrimidine derivatives as novel inhibitors of ataxia telangiectasia and rad3 related protein (ATR).

The ATR pathway is a critical mediator of the replication stress response in cells. In aberrantly proliferating cancer cells, this pathway can help maintain sufficient genomic integrity for cancer cell progression. Herein we describe the discovery of 19, a pyrazolopyrimidine-containing inhibitor of ATR via a strategic repurposing of compounds targeting PI3K.

Temozolomide analogs with improved brain/plasma ratios - Exploring the possibility of enhancing the therapeutic index of temozolomide.

Temozolomide is a chemotherapeutic agent that is used in the treatment of glioblastoma and other malignant gliomas. It acts through DNA alkylation, but treatment is limited by its systemic toxicity and neutralization of DNA alkylation by upregulation of the O-methylguanine-DNA methyltransferase gene. Both of these limiting factors can be addressed by achieving higher concentrations of TMZ in the brain.

Role of the androgen receptor in breast cancer and preclinical analysis of enzalutamide.

Introduction: The androgen receptor (AR) is widely expressed in breast cancers and has been proposed as a therapeutic target in estrogen receptor alpha (ER) negative breast cancers that retain AR. However, controversy exists regarding the role of AR, particularly in ER + tumors. Enzalutamide, an AR inhibitor that impairs nuclear localization of AR, was used to elucidate the role of AR in preclinical models of ER positive and negative breast cancer.

Enzalutamide, an androgen receptor signaling inhibitor, induces tumor regression in a mouse model of castration-resistant prostate cancer.

Background: Enzalutamide (formerly MDV3100 and available commercially as Xtandi), a novel androgen receptor (AR) signaling inhibitor, blocks the growth of castration-resistant prostate cancer (CRPC) in cellular model systems and was shown in a clinical study to increase survival in patients with metastatic CRPC. Enzalutamide inhibits multiple steps of AR signaling: binding of androgens to AR, AR nuclear translocation, and association of AR with DNA. Here, we investigate the effects of enzalutamide on AR signaling, AR-dependent gene expression and cell apoptosis.

Cognition-enhancing properties of Dimebon in a rat novel object recognition task are unlikely to be associated with acetylcholinesterase inhibition or N-methyl-D-aspartate receptor antagonism.

Dimebon (dimebolin) treatment enhances cognition in patients with Alzheimer's disease (AD) or Huntington's disease. Although Dimebon was originally thought to improve cognition and memory through inhibition of acetylcholinesterase (AChE) and the N-methyl-d-aspartate (NMDA) receptor, the low in vitro affinity for these targets suggests that these mechanisms may not contribute to its clinical effects. To test this hypothesis, we assessed whether Dimebon enhances cognition in rats and if such an action is related to either mechanism or additional candidate mechanisms.

Topical alpha-selective p38 MAP kinase inhibition reduces acute skin inflammation in guinea pig.

Certain skin pathologies, including psoriasis, are thought to be immune-mediated inflammatory diseases. Available literature clearly indicates the involvement of inflammatory cells (neutrophils, T cells, and macrophages), their cytokines, and the p38 mitogen-activated protein kinase (MAPK) signaling pathway in the pathophysiology of psoriasis. Neutrophils play an important role in the formation of acute inflammatory changes in psoriasis.

Clinical implications of defective B-type natriuretic peptide.

Our understanding of the natriuretic peptide system continues to evolve rapidly. B-type natriuretic peptide (BNP), originally thought to be a simple volume-regulating hormone that is produced in response to cardiac stretch, has been shown to also play important roles in modulating bronchodilation, endothelial function, and cardiac remodeling. Recent data demonstrate that elevated levels of BNP in patients with heart failure do not represent a simple ratcheting up of normal production in response to increased stimulus.

Long-term effects of B-type natriuretic peptide infusion after acute myocardial infarction in a rat model.

Introduction: The effects of exogenous B-type natriuretic peptide (BNP) on postmyocardial infarction (MI) are not known. We tested the hypothesis that in vivo infusion of BNP would improve cardiac function and affect left ventricular (LV) remodeling in an experimental model of MI.

Methods: MI was induced by coronary ligation in rats and confirmed by echocardiography.

Detection of endogenous B-type natriuretic peptide at very low concentrations in patients with heart failure.

Background: The myocardium secretes B-type natriuretic peptide (BNP) in response to stimuli associated with heart failure (HF). However, high immunoreactive-BNP levels in patients with HF are associated with a paradoxical lack of natriuretic response. We hypothesized that commercially available assays for immunoreactive BNP do not reflect the bioactivity of the natriuretic peptide system, because they measure both unprocessed inactive pro-BNP and mature BNP 1-32.

Prolonged effects of B-type natriuretic peptide infusion on cardiac remodeling after sustained myocardial injury.

B-type natriuretic peptide (BNP) is an established first-line therapy for acute decompensated heart failure (HF), but its efficacy in preventing left ventricular (LV) remodeling after myocardial injury is unknown. The goal of this study was to evaluate the effects of BNP therapy on remodeling after ischemic injury in an awake canine model. Dogs were chronically instrumented for hemodynamics.

p38alpha-selective MAP kinase inhibitor reduces tumor growth in mouse xenograft models of multiple myeloma.

Multiple myeloma (MM) is a clonal plasma cell malignancy, which is currently incurable. Therefore, new mono- or combined therapy treatment regimens in the early and advanced phases of MM are urgently needed to combat this disease. Recently, p38 mitogen-activated protein kinase (MAPK) has been implicated as playing an important role in MM.

p38 MAPK inhibition reduces diabetes-induced impairment of wound healing.

In healthy tissue, a wound initiates an inflammatory response characterized by the presence of a hematoma, infiltration of inflammatory cells into the wound and, eventually, wound healing. In pathological conditions like diabetes mellitus, wound healing is impaired by the presence of chronic nonresolving inflammation. p38 mitogen-activated protein kinase (MAPK) inhibitors have demonstrated anti-inflammatory effects, primarily by inhibiting the expression of inflammatory cytokines and regulating cellular traffic into wounds.

Transforming growth factor-beta blockade down-regulates the renin-angiotensin system and modifies cardiac remodeling after myocardial infarction.

After myocardial infarction (MI), the heart may undergo progressive ventricular remodeling, resulting in a deterioration of cardiac function. TGF-beta is a key cytokine that both initiates and terminates tissue repair, and its sustained production underlies the development of tissue fibrosis, particularly after MI. We investigated the effects of a novel orally active specific inhibitor of the TGF-beta receptor 1 (SD-208) in an experimental model of MI.

Role of p38 mitogen activated protein kinase in a model of osteosarcoma-induced pain.

The focus of this work was to examine the potential role of p38 mitogen activated protein kinase (p38) in a mouse model of bone cancer (osteosarcoma) pain. To generate osteosarcoma and sham animals, osteosarcoma cells or medium were injected into the medullary canal of the femur. Initially, ipsilateral tactile allodynia was observed in both groups, but by 12 days post-surgery, thresholds in the sham group returned towards baseline while hypersensitivity in the osteosarcoma group lasted throughout the study.

Antitumor activity of TGF-beta inhibitor is dependent on the microenvironment.

Pancreatic cancer is one of the deadliest forms of cancer and effective treatment remains a clinical challenge. Transforming growth factor-beta (TGF-beta) has important roles in primary tumor progression and in promoting metastasis, and has become an attractive target for therapy. Previously, we reported that treatment of pancreatic cancer cells in vitro with SD-208, a small molecule inhibitor of the TGF-beta receptor I kinase (TGF-betaRI), inhibited expression of genes associated with tumor progression and inhibited invasiveness in a cell-based assay.

Pharmacological properties of SD-282 - an alpha-isoform selective inhibitor for p38 MAP kinase.

The effects of small-molecule p38 inhibitors in numerous models of different disease states have been published, including those of SD-282, an indole-5-carboxamide inhibitor. The aim of the present study was to evaluate the pharmacological activity of SD-282 on cytokine production in vitro as well as in 2 in vivo models of inflammation in order to illuminate the role of this particular inhibitor in diverse disease states. The results presented here provide further characterization of SD-282 and provide a context in which to interpret the activity of this p38 inhibitor in models of arthritis, pain, myocardial injury, sepsis and asthma; all of which have an inflammatory component.

Selective p38α mitogen-activated protein kinase inhibitor attenuates lung inflammation and fibrosis in IL-13 transgenic mouse model of asthma.

p38 Mitogen-activated protein kinase (MAPK) plays a critical role in the activation of inflammatory cells. We investigated the anti-inflammatory effects of a p38α-selective MAPK inhibitor (SD-282) in a mouse transgenic (CC10:IL-13) asthma model. The CC-10-driven over-expression of IL-13 in the mouse lung/airway has been shown to result in a remarkable phenotype recatitulating many features of asthma and characterized by eosinophilic and mononuclear inflammation, with airway epithelial cell hypertrophy, mucus cell metaplasia, the hyperproduction of neutral and acidic mucus, the deposition of Charcot-Leyden-like crystal, and airway sub-epitheilial fibrosis.

p38alpha-selective mitogen-activated protein kinase inhibitor SD-282 reduces inflammation in a subchronic model of tobacco smoke-induced airway inflammation.

Chronic obstructive pulmonary disease (COPD) is characterized by pulmonary inflammation, which is relatively insensitive to inhaled corticosteroids. The extent of the pulmonary inflammation in COPD correlates with disease severity, and it is thought to play a significant role in disease progression. We have evaluated a selective p38alpha-selective mitogen-activated protein kinase (MAPK) inhibitor, indole-5-carboxamide (ATP-competitive inhibitor of p38 kinase) (SD-282), in an 11-day model of tobacco smoke (TS)-induced pulmonary inflammation in A/J mice, by using dexamethasone as a reference steroid.

Recombinant vascular endothelial growth factor 121 attenuates hypertension and improves kidney damage in a rat model of preeclampsia.

Inhibitors of angiogenic factors are known to be upregulated, and their levels increase in the maternal circulation before the onset of preeclampsia. We reproduced a previously characterized model of preeclampsia by adenoviral overexpression of the soluble vascular endothelial growth factor (VEGF) receptor sFlt-1 (also referred to as sVEGFR-1) in pregnant and nonpregnant Sprague-Dawley rats. Animals were treated with VEGF121 at 0, 100, 200, or 400 microg/kg once or twice daily (n=8 per group; 64 total) and compared with normal control animals (n=4 per group) by examination of systolic blood pressure, urinary albumin and creatinine, renal histopathology, and glomerular gene expression profiling.

Inhibiting TGF-beta signaling restores immune surveillance in the SMA-560 glioma model.

Transforming growth factor-beta (TGF-beta) is a proinvasive and immunosuppressive cytokine that plays a major role in the malignant phenotype of gliomas. One novel strategy of disabling TGF-beta activity in gliomas is to disrupt the signaling cascade at the level of the TGF-beta receptor I (TGF-betaRI) kinase, thus abrogating TGF-beta-mediated invasiveness and immune suppression. SX-007, an orally active, small-molecule TGF-betaRI kinase inhibitor, was evaluated for its therapeutic potential in cell culture and in an in vivo glioma model.

Inhibition of p38alpha mitogen-activated protein kinase prevents the development of osteolytic bone disease, reduces tumor burden, and increases survival in murine models of multiple myeloma.

The bone microenvironment plays a critical role in supporting the growth and survival of multiple myeloma as well as in the development of osteolytic bone disease. Signaling through p38alpha mitogen-activated protein kinase (MAPK) mediates synthesis of multiple myeloma cell growth factors, and its inhibition reduces proliferation in vitro. However, it is unclear whether targeting p38alpha MAPK prevents multiple myeloma growth and the development of bone disease in vivo.

B-Type natriuretic peptide inhibited angiotensin II-stimulated cholesterol biosynthesis, cholesterol transfer, and steroidogenesis in primary human adrenocortical cells.

In this study, we demonstrate that B-type natriuretic peptide (BNP) opposed angiotensin II (Ang II)-stimulated de novo cholesterol biosynthesis, cellular cholesterol uptake, cholesterol transfer to the inner mitochondrial membrane, and steroidogenesis, which are required for biosynthesis of steroid hormones such as aldosterone and cortisol in primary human adrenocortical cells. BNP dose-dependently stimulated intracellular cGMP production with an EC(50) of 11 nm, implying that human adrenocortical cells express the guanylyl cyclase A receptor. cDNA microarray and real-time RT-PCR analyses revealed that BNP inhibited Ang II-stimulated genes related to cholesterol biosynthesis (acetoacetyl coenzyme A thiolase, HMG coenzyme A synthase 1, HMG coenzyme A reductase, isopentenyl-diphosphate Delta-isomerase, lanosterol synthase, sterol-4C-methyl oxidase, and emopamil binding protein/sterol isomerase), cholesterol uptake from circulating lipoproteins (scavenger receptor class B type I and low-density lipoprotein receptor), cholesterol transfer to the inner mitochondrial membrane (steroidogenic acute regulatory protein), and steroidogenesis (ferredoxin 1,3beta-hydroxysteroid dehydrogenase, glutathione transferase A3, CYP19A1, CYP11B1, and CYP11B2).

Evidence for functional heterogeneity of circulating B-type natriuretic peptide.

Objectives: These studies describe molecular forms of circulating B-type natriuretic peptide (BNP) as well as their biological activity.

Background: Increased circulating levels of immunoreactive BNP correlate with the severity of heart failure and are considered a sensitive biomarker. However, little is known about the molecular forms of circulating BNP and their biological activity.