A5040255389- Ubiquitin and proteasome pathways
- Cancer, Hypoxia, and Metabolism
- Computational Drug Discovery Methods
- SARS-CoV-2 and COVID-19 Research
- COVID-19 Clinical Research Studies
- Mitochondrial Function and Pathology
- Protein Degradation and Inhibitors
- Monoclonal and Polyclonal Antibodies Research
- Microbial Natural Products and Biosynthesis
- Pharmacological Receptor Mechanisms and Effects
- Multiple Myeloma Research and Treatments
- SARS-CoV-2 detection and testing
- Viral Infectious Diseases and Gene Expression in Insects
- 3D Printing in Biomedical Research
- Histone Deacetylase Inhibitors Research
- Virus-based gene therapy research
- Autophagy in Disease and Therapy
- Pluripotent Stem Cells Research
- Epigenetics and DNA Methylation
- Mosquito-borne diseases and control
- Advanced Biosensing Techniques and Applications
- Cancer therapeutics and mechanisms
- Genomics and Chromatin Dynamics
- Lung Cancer Research Studies
- Calcium signaling and nucleotide metabolism
National Institutes of Health
2017-2025
National Center for Advancing Translational Sciences
2017-2025
Howard Hughes Medical Institute
2023
National Cancer Institute
2023
Center for Cancer Research
2023
Novartis (Switzerland)
2012
AstraZeneca (United States)
2010
Raritan Bay Medical Center
2003
Diffuse midline gliomas (DMGs) are universally lethal malignancies occurring chiefly during childhood and involving structures of the central nervous system, including thalamus, pons, spinal cord. These molecularly related cancers characterized by high prevalence histone H3K27M mutation. In search effective therapeutic options, we examined multiple DMG cultures in sequential quantitative high-throughput screens (HTS) 2706 approved investigational drugs. This effort generated 19,936...
Significance COVID-19 has caused more than 2.5 million deaths worldwide. It is imperative that we develop therapies can mitigate the effect of disease. While searching for individual drugs this purpose been met with difficulties, synergistic drug combinations offer a promising alternative. However, lack high-quality training data pertaining to makes it challenging use existing machine learning methods effective novel combination prediction tasks. Our proposed approach addresses challenge by...
Antiviral drug development for coronavirus disease 2019 (COVID-19) is occurring at an unprecedented pace, yet there are still limited therapeutic options treating this disease. We hypothesized that combining drugs with independent mechanisms of action could result in synergy against SARS-CoV-2, thus generating better antiviral efficacy. Using silico approaches, we prioritized 73 combinations 32 potential activity SARS-CoV-2 and then tested them vitro. Sixteen synergistic eight antagonistic...
The National Center for Advancing Translational Sciences (NCATS) has developed an online open science data portal its COVID-19 drug repurposing campaign - named OpenData with the goal of making across a range SARS-CoV-2 related assays available in real-time. cover wide spectrum life cycle, including both viral and human (host) targets. In total, over 10,000 compounds are being tested full concentration-response ranges from multiple annotated small molecule libraries, approved drug,...
Drug repurposing is a rapid approach to identify therapeutics for the treatment of emerging infectious diseases such as COVID-19. To address urgent need options, we carried out quantitative high-throughput screen using SARS-CoV-2 cytopathic assay with compound collection 8,810 approved and investigational drugs, mechanism-based bioactive compounds, natural products. Three hundred nineteen compounds anti-SARS-CoV-2 activities were identified confirmed, including 91 drugs 49 drugs. The 230...
Understanding the SARS-CoV-2 virus' pathways of infection, virus–host–protein interactions, and mechanisms virus-induced cytopathic effects will greatly aid in discovery design new therapeutics to treat COVID-19. Chloroquine hydroxychloroquine, extensively explored as clinical agents for COVID-19, have multiple cellular including alkalizing lysosomes blocking autophagy well exhibiting dose-limiting toxicities patients. Therefore, we evaluated additional lysosomotropic compounds identify an...
The COVID-19 pandemic, caused by SARS-CoV-2, is a pressing public health emergency garnering rapid response from scientists across the globe. Host cell invasion initiated through direct binding of viral spike protein to host receptor angiotensin-converting enzyme 2 (ACE2). Disrupting protein–ACE2 interaction potential therapeutic target for treating COVID-19. We have developed proximity-based AlphaLISA assay measure SARS-CoV-2 domain (RBD) ACE2. Utilizing this platform, drug-repurposing...
Abstract Combination of anti-cancer drugs is broadly seen as way to overcome the often-limited efficacy single agents. The design and testing combinations are however very challenging. Here we present a uniquely large dataset screening over 5000 targeted agent across 81 non-small cell lung cancer lines. Our analysis reveals profound heterogeneity response tumor models. Notably, rarely result in strong gain range observable with Importantly, activity agents more often when co-targeting...
Abstract SARS-CoV-2 is a new type of coronavirus capable rapid transmission and causing severe clinical symptoms; much which has unknown biological etiology. It prompted researchers to rapidly mobilize their efforts towards identifying developing anti-viral therapeutics vaccines. Discovering understanding the virus’ pathways infection, host-protein interactions, cytopathic effects will greatly aid in design treat COVID-19. While it known that chloroquine hydroxychloroquine, extensively...
Abstract Colorectal cancers (CRCs) are prevalent worldwide, yet current treatments remain inadequate. Using chemical genetic screens, we identify that co-inhibition of topoisomerase I (TOP1) and NEDD8 is synergistically cytotoxic in human CRC cells. Combination the TOP1 inhibitor irinotecan or its bioactive metabolite SN38 with NEDD8-activating enzyme pevonedistat exhibits synergy patient-derived organoids xenografts. Mechanistically, show blocks ubiquitin/proteasome-dependent repair...
Effective small molecule therapies to combat the SARS-CoV-2 infection are still lacking as COVID-19 pandemic continues globally. High throughput screening assays needed for lead discovery and optimization of inhibitors. In this work, we have applied viral pseudotyping establish a cell-based entry assay. Here, pseudotyped particles (PP) contain spike in membrane enveloping both murine leukemia virus (MLV) gag-pol polyprotein luciferase reporter RNA. Upon addition PP HEK293-ACE2 cells, protein...
Small cell lung cancer (SCLC) is a recalcitrant malignancy with limited treatment options. Bromodomain and extraterminal domain inhibitors (BETis) have shown promising preclinical activity in SCLC, but the broad sensitivity spectrum limits their clinical prospects. Here, we performed unbiased high-throughput drug combination screens to identify therapeutics that could augment antitumor activities of BETis SCLC. We found multiple drugs targeting PI-3K–AKT–mTOR pathway synergize BETis, among...
Abstract Background MiT-Renal Cell Carcinoma (RCC) is characterized by genomic translocations involving microphthalmia-associated transcription factor (MiT) family members TFE3 , TFEB or MITF . MiT-RCC represents a specific subtype of sporadic RCC that predominantly seen in young patients and can present with heterogeneous histological features making diagnosis challenging. Moreover, the disease biology this aggressive cancer poorly understood there no accepted standard care therapy for...
Abstract Current treatment options for metastatic adrenocortical carcinoma (ACC) have limited efficacy, despite the common use of mitotane and cytotoxic agents. This study aimed to identify novel therapeutic ACC. An extensive drug screen was conducted compounds with potential activity against ACC cell lines. We further investigated mechanism action identified compound, TAK-243, its synergistic effects current therapeutics, efficacy in models including patient-derived organoids mouse...
Natural products and their derivatives continue to be wellsprings of nascent therapeutic potential. However, many laboratories have limited resources for biological evaluation, leaving previously isolated or synthesized compounds largely completely untested. To address this issue, the Canvass library natural was assembled, in collaboration with academic industry researchers, quantitative high-throughput screening (qHTS) across a diverse set cell-based biochemical assays. Characterization...
Abstract COVID-19 is undoubtedly the most impactful viral disease of current century, afflicting millions worldwide. As yet, there not an approved vaccine, as well limited options from existing drugs for treating this disease. We hypothesized that combining with independent mechanisms action could result in synergy against SARS-CoV-2. Using silico approaches, we prioritized 73 combinations 32 potential activity SARS-CoV-2 and then tested them vitro . Overall, identified 16 synergistic 8...
Abstract Pancreatic cancer treatment often relies on multi-drug regimens, but optimal combinations remain elusive. This study evaluates predictive approaches to identify synergistic drug using a dataset from the National Center for Advancing Translational Sciences (NCATS). Screening 496 of 32 anticancer compounds against PANC-1 cells experimentally determined degree synergism and antagonism. Three research groups (NCATS, University North Carolina, Massachusetts Institute Technology) leverage...
Abstract The COVID-19 pandemic, caused by SARS-CoV-2, is a pressing public health emergency garnering rapid response from scientists across the globe. Host cell invasion initiated through direct binding of viral spike protein to host receptor angiotensin-converting enzyme 2 (ACE2). Disrupting spike-ACE2 interaction potential therapeutic target for treating COVID-19. We have developed proximity-based AlphaLISA assay measure SARS-CoV-2 Receptor Binding Domain (RBD) ACE2. Utilizing this...
Abstract Drug repurposing is a rapid approach to identifying therapeutics for the treatment of emerging infectious diseases such as COVID-19. To address urgent need options, we carried out quantitative high-throughput screen using SARS-CoV-2 cytopathic assay with compound collection 8,810 approved and investigational drugs, mechanism-based bioactive compounds, natural products. Three hundred nineteen compounds anti-SARS-CoV-2 activities were identified confirmed, including 91 drug 49 drugs....
SARS-CoV-2 entry into host cells relies on the spike (S) protein binding to human ACE2 receptor. In this study, we investigated structural dynamics of viral S at fusion peptide (FP) domain and small molecule for therapeutics development. Following comparative modeling analysis docking studies our previously identified inhibitor chlorcyclizine, performed a pharmacophore-based virtual screen two novel chemotypes inhibitors targeting FP. The compounds were evaluated in pseudoparticle assay...
An approach is described for high-throughput quality assessment of drug candidate libraries using acoustic ejection high-resolution mass spectrometry (AEMS). Sample introduction from 1536-well plates demonstrated this application 2.5 nL acoustically dispensed sample droplets into an Open Port Interface (OPI) with pneumatically assisted electrospray ionization at a rate one second per sample. Both positive and negative are shown to be essential extend the compound coverage protease...
Abstract Multiple myeloma, a hematopoietic malignancy of terminally differentiated B cells, is the second most common hematological after leukemia. While patients have benefited from numerous advances in treatment recent years resulting significant increases to average survival time following diagnosis, myeloma remains incurable and relapse common. To help identify novel therapeutic agents with efficacy against disease search for biomarkers associated differential response treatment,...
Neutralizing antibodies targeting the SARS-CoV-2 spike protein have shown a great preventative/therapeutic potential. Here, we report rapid and efficient strategy for development design of neutralizing humanized nanobody constructs with sub-nanomolar affinities nanomolar potencies. CryoEM-based structural analysis nanobodies in complex revealed two distinct binding modes. The most potent nanobody, RBD-1-2G(NCATS-BL8125), tolerates N501Y RBD mutation remains capable B.1.1.7 (Alpha) variant....