4,690 results match your criteria small-molecule screen

Development of succinimide-based inhibitors for the mitochondrial rhomboid protease PARL.

Bioorg Med Chem Lett 2021 Jul 23:128290. Epub 2021 Jul 23.

Department of Chemistry and Biochemistry, Oberlin College, Oberlin, OH Room A263, Science Center, 119 Woodland St., Oberlin, OH 44074, USA.

While the biochemistry of rhomboid proteases has been extensively studied since their discovery two decades ago, efforts to define the physiological roles of these enzymes are ongoing and would benefit from chemical probes that can be used to manipulate the functions of these proteins in their native settings. Here, we describe the use of activity-based protein profiling (ABPP) technology to conduct a targeted screen for small-molecule inhibitors of the mitochondrial rhomboid protease PARL, which plays a critical role in regulating mitophagy and cell death. We synthesized a series of succinimide-containing sulfonyl esters and sulfonamides and discovered that these compounds serve as inhibitors of PARL with the most potent sulfonamides having submicromolar affinity for the enzyme. Read More

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Acoustic Ejection Mass Spectrometry: A Fully Automatable Technology for High-Throughput Screening in Drug Discovery.

SLAS Discov 2021 Jul 26:24725552211028135. Epub 2021 Jul 26.

Drug Discovery Sciences, Boehringer Ingelheim Pharma, Biberach an der Riß, Germany.

Acoustic droplet ejection (ADE)-open port interface (OPI)-mass spectrometry (MS) has recently been introduced as a versatile analytical method that combines fast and contactless acoustic sampling with sensitive and accurate electrospray ionization (ESI)-MS-based analyte detection. The potential of the technology to provide label-free measurements in subsecond analytical cycle times makes it an attractive option for high-throughput screening (HTS). Here, we report the first implementation of ADE-OPI-MS in a fully automated HTS environment, based on the example of a biochemical assay aiming at the identification of small-molecule inhibitors of the cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) synthase (cGAS). Read More

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Computational investigation of FDA approved drugs as selective PARP-1 inhibitors by targeting BRCT domain for cancer therapy.

J Mol Graph Model 2021 Apr 6;108:107919. Epub 2021 Apr 6.

Postgraduate and Research Department of Botany, Arignar Anna Government Arts College, Villupuram, Tamil Nadu, India.

Poly(ADP-ribose) polymerase-1 is a promising target for the treatment of cancer due to its involvement in base excision repair pathways for repairing DNA single-strand breaks. However, available PARP-1 inhibitors target a highly conserved PARPs catalytic domain, which causes toxicity due to the off-target activity. Therefore, the present study was hypothesized to identify selective inhibitors by targeting specific protein-protein interacting (PPI) PARP-1 BRCT domain. Read More

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EGFR activation limits the response of liver cancer to lenvatinib.

Nature 2021 Jul 21;595(7869):730-734. Epub 2021 Jul 21.

State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Hepatocellular carcinoma (HCC)-the most common form of liver cancer-is an aggressive malignancy with few effective treatment options. Lenvatinib is a small-molecule inhibitor of multiple receptor tyrosine kinases that is used for the treatment of patients with advanced HCC, but this drug has only limited clinical benefit. Here, using a kinome-centred CRISPR-Cas9 genetic screen, we show that inhibition of epidermal growth factor receptor (EGFR) is synthetic lethal with lenvatinib in liver cancer. Read More

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3D tumor spheroid microarray for high-throughput, high-content natural killer cell-mediated cytotoxicity.

Commun Biol 2021 Jul 21;4(1):893. Epub 2021 Jul 21.

Department of Chemical and Biological Engineering, and Center for Biotechnology & Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, USA.

Immunotherapy has emerged as a promising approach to treating several forms of cancer. Use of immune cells, such as natural killer (NK) cells, along with small molecule drugs and antibodies through antibody dependent cell-mediated cytotoxicity (ADCC) has been investigated as a potential combination therapy for some difficult to treat solid tumors. Nevertheless, there remains a need to develop tools that support co-culture of target cancer cells and effector immune cells in a contextually relevant three-dimensional (3D) environment to provide a rapid means to screen for and optimize ADCC-drug combinations. Read More

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Chemical screen identifies diverse and novel HDAC inhibitors as repressors of NUT function: implications for NUT carcinoma pathogenesis and treatment.

Mol Cancer Res 2021 Jul 20. Epub 2021 Jul 20.

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School

NUT carcinoma (NC), characterized most commonly by the BRD4-NUTM1 fusion, is a rare, aggressive variant of squamous carcinoma with no effective treatment. BRD4-NUT drives growth and maintains the poorly differentiated state of NC by activating pro-growth genes such as MYC, through the formation of massive, hyperacetylated, super-enhancer-like domains termed megadomains. BRD4-NUT-mediated hyperacetylation of chromatin is facilitated by the chromatin-targeting tandem bromodomains of BRD4, combined with NUT, which recruits the histone acetyltransferase, p300. Read More

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A small molecule that induces translational readthrough of CFTR nonsense mutations by eRF1 depletion.

Nat Commun 2021 07 16;12(1):4358. Epub 2021 Jul 16.

Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham (UAB), Birmingham, AL, USA.

Premature termination codons (PTCs) prevent translation of a full-length protein and trigger nonsense-mediated mRNA decay (NMD). Nonsense suppression (also termed readthrough) therapy restores protein function by selectively suppressing translation termination at PTCs. Poor efficacy of current readthrough agents prompted us to search for better compounds. Read More

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Discovery, Structure-Activity Relationships, and In Vivo Evaluation of Novel Aryl Amides as Brain Penetrant Adaptor Protein 2-Associated Kinase 1 (AAK1) Inhibitors for the Treatment of Neuropathic Pain.

J Med Chem 2021 Jul 16. Epub 2021 Jul 16.

Department of Small Molecule Drug Discovery, Bristol Myers Squibb Company, Research and Development, Wallingford, Connecticut 06492, United States.

Effective treatment of chronic pain, in particular neuropathic pain, without the side effects that often accompany currently available treatment options is an area of significant unmet medical need. A phenotypic screen of mouse gene knockouts led to the discovery that adaptor protein 2-associated kinase 1 (AAK1) is a potential therapeutic target for neuropathic pain. The synthesis and optimization of structure-activity relationships of a series of aryl amide-based AAK1 inhibitors led to the identification of , a brain penetrant, AAK1-selective inhibitor that proved to be a valuable tool compound. Read More

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Identification of four key biomarkers and small molecule drugs in nasopharyngeal carcinoma by weighted gene co-expression network analysis.

Xi Pan Jian-Hao Liu

Bioengineered 2021 Dec;12(1):3647-3661

School of Pharmaceutical Sciences of Central South University, Changsha, 410078, China.

Nasopharyngeal carcinoma (NPC) is a heterogeneous carcinoma whose underlying molecular mechanisms involved in tumor initiation, progression, and migration are largely unclear. The aim of the present study was to identify key biomarkers and small-molecule drugs for screening, diagnosing, and treating NPC via gene expression profile analysis. Raw microarray data was used to identify 430 differentially expressed genes (DEGs) in the Gene Expression Omnibus (GEO) database. Read More

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December 2021

Classifying molecular phenotypes of variants for pathogenic properties and to guide therapeutic development.

JIMD Rep 2021 Jul 28;60(1):56-66. Epub 2021 Mar 28.

Genetics and Genome Sciences Department, School of Medicine Case Western Reserve University Cleveland Ohio USA.

Due to advances in sequencing technologies, identification of genetic variants is rapid. However, the functional consequences of most genomic variants remain unknown. Consequently, variants of uncertain significance (VUS) that appear in clinical DNA diagnostic reports lack sufficient data for interpretation. Read More

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Recent advances in herbal combination nanomedicine for cancer: Delivery technology and therapeutic outcomes.

Expert Opin Drug Deliv 2021 Jul 13. Epub 2021 Jul 13.

Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.

: The use of herbal compounds in cancer therapy has great potential to promote the efficacy of current cancer therapeutic strategies. Herbal compounds were successfully reported to enhance tumor cells sensitization to the action of chemo-, hormonal- and gene-therapeutic agents different mechanisms. Herbal ingredients can affect different signaling pathways, reduce the toxic side effects or inhibit the efflux of anticancer drugs. Read More

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Morphological screening of mesenchymal mammary tumor organoids to identify drugs that reverse epithelial-mesenchymal transition.

Nat Commun 2021 07 12;12(1):4262. Epub 2021 Jul 12.

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.

The epithelial-mesenchymal transition (EMT) has been implicated in conferring stem cell properties and therapeutic resistance to cancer cells. Therefore, identification of drugs that can reprogram EMT may provide new therapeutic strategies. Here, we report that cells derived from claudin-low mammary tumors, a mesenchymal subtype of triple-negative breast cancer, exhibit a distinctive organoid structure with extended "spikes" in 3D matrices. Read More

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Small-molecule modulators of INAVA cytosolic condensate and cell-cell junction assemblies.

J Cell Biol 2021 Sep 12;220(9). Epub 2021 Jul 12.

Division of Gastroenterology and Nutrition, Department of Pediatrics, Boston Children's Hospital, Boston, MA.

Epithelial cells lining mucosal surfaces distinctively express the inflammatory bowel disease risk gene INAVA. We previously found that INAVA has dual and competing functions: one at lateral membranes where it affects mucosal barrier function and the other in the cytosol where INAVA enhances IL-1β signal transduction and protein ubiquitination and forms puncta. We now find that IL-1β-induced INAVA puncta are biomolecular condensates that rapidly assemble and physiologically resolve. Read More

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September 2021

Electrochemical flow injection analysis of the interaction between pyrroloquinoline quinone (PQQ) and α-synuclein peptides related to Parkinson's disease.

Analyst 2021 Jul 18;146(14):4545-4556. Epub 2021 Jun 18.

Department of Physical and Environmental Sciences, University of Toronto Scarborough, 1265 Military Trail, Toronto, ON M1C 1A4, Canada.

α-Synuclein (α-syn) is a hallmark protein of Parkinson's disease (PD). The aggregation process of α-syn has been heavily associated with the pathogenesis of PD. With the exponentially growing number of potential therapeutic compounds that can inhibit the aggregation of α-syn, there is now a significant demand for a high-throughput analysis system. Read More

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Fast Mek1 Hit Identification with TRIC Technology Correlates Well with Other Biophysical Methods.

SLAS Discov 2021 Jul 8:24725552211026267. Epub 2021 Jul 8.

Application Team, NanoTemper Technologies GmbH, Munich, Germany.

The variety and complexity of drug targets are expanding rapidly. At the same time, there is significant interest in exploring a larger chemical space to identify new candidates. Fragment-based screening (FBS) has emerged as a popular alternative to traditional high-throughput screening campaigns to identify such drug candidates. Read More

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A new thinking: extended application of genomic selection to screen multiomics data for development of novel hypoxia-immune biomarkers and target therapy of clear cell renal cell carcinoma.

Brief Bioinform 2021 May 11. Epub 2021 May 11.

First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.

Increasing evidences show the clinical significance of the interaction between hypoxia and immune in clear cell renal cell carcinoma (ccRCC) microenvironment. However, reliable prognostic signatures based on a combination of hypoxia and immune have not been well established. Moreover, many studies have only used RNA-seq profiles to screen the prognosis feature of ccRCC. Read More

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Screening Reveals Sterol Derivatives with Pro-Differentiation, Pro-Survival, or Potent Cytotoxic Effects on Oligodendrocyte Progenitor Cells.

ACS Chem Biol 2021 Jul 7;16(7):1288-1297. Epub 2021 Jul 7.

Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, United States.

Inducing the formation of new oligodendrocytes from oligodendrocyte progenitor cells (OPCs) represents a potential approach to repairing the loss of myelin observed in multiple sclerosis and other diseases. Recently, we demonstrated that accumulation of specific cholesterol precursors, 8,9-unsaturated sterols, is a dominant mechanism by which dozens of small molecules enhance oligodendrocyte formation. Here, we evaluated a library of 56 sterols and steroids to evaluate whether other classes of bioactive sterol derivatives may also influence mouse oligodendrocyte precursor cell (OPC) differentiation or survival. Read More

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A small molecule, ACAi-028, with anti-HIV-1 activity targets a novel hydrophobic pocket on HIV-1 capsid.

Antimicrob Agents Chemother 2021 Jul 6:AAC0103921. Epub 2021 Jul 6.

Department of Hematology, Rheumatology, and Infectious Diseases, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.

The human immunodeficiency virus type 1 (HIV-1) capsid (CA) is an essential viral component of HIV-1 infection and an attractive therapeutic target for antivirals. We report that a small molecule, ACAi-028, inhibits HIV-1 replication by targeting a hydrophobic pocket in the N-terminal domain of CA (CA-NTD). ACAi-028 is one of more than 40 candidate anti-HIV-1 compounds identified by screening and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Read More

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[Mass spectrometry imaging technology and its application in breast cancer research].

Se Pu 2021 Jun;39(6):578-587

State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong 999077, China.

The incidence of breast cancer, one of the most common malignancies affecting women, is increasing significantly worldwide. Given the rapid development of medical technology, early and effective diagnostic methods should be able to improve the survival rate and quality of life of patients suffering from disease. However, although existing treatment options, including chemotherapy and endocrine therapies, have greatly improved the survival of patients, disease recurrence in the long term remains a challenge. Read More

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A new high-content screening assay of the entire hepatitis B virus life cycle identifies novel antivirals.

JHEP Rep 2021 Aug 30;3(4):100296. Epub 2021 Apr 30.

Applied Molecular Virology Laboratory, Institut Pasteur Korea, Seongnam-si, South Korea.

Background & Aims: Chronic hepatitis B is an incurable disease. Addressing the unmet medical need for therapies has been hampered by a lack of suitable cell culture models to investigate the HBV life cycle in a single experimental setup. We sought to develop a platform suitable to investigate all aspects of the entire HBV life cycle. Read More

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Medullary Thyroid Cancer - Feature Review and Update on Systemic Treatment.

Acta Clin Croat 2020 Jun;59(Suppl 1):50-59

1Department of Oncology and Nuclear Medicine, Sestre Milosrdnice University Hospital Centre, Zagreb, Croatia; 2University of Zagreb, School of Medicine; 3University of Zagreb, School of Dental Medicine.

Medullary thyroid carcinoma (MTC) is a rare malignancy that originates from parafollicular (C cells) of the thyroid and accounts for 2-4% of all thyroid malignancies. MTC may be sporadic or inherited, the latter as part of the MEN 2 syndromes. Germline mutations in the proto-oncogene (REarranged during Transfection) are driver mutations in hereditary MTC, whereas somatic mutations and, less frequently, mutations, have been described in tumor tissues of sporadic MTC. Read More

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High-Throughput Screening to Identify Small Molecules That Selectively Inhibit APOL1 Protein Level in Podocytes.

SLAS Discov 2021 Jul 3:24725552211026245. Epub 2021 Jul 3.

Screening, Target and Compound Profiling, Merck & Co., Inc., Kenilworth, NJ, USA.

High-throughput phenotypic screening is a key driver for the identification of novel chemical matter in drug discovery for challenging targets, especially for those with an unclear mechanism of pathology. For toxic or gain-of-function proteins, small-molecule suppressors are a targeting/therapeutic strategy that has been successfully applied. As with other high-throughput screens, the screening strategy and proper assays are critical for successfully identifying selective suppressors of the target of interest. Read More

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pdCSM-cancer: Using Graph-Based Signatures to Identify Small Molecules with Anticancer Properties.

J Chem Inf Model 2021 Jul 2;61(7):3314-3322. Epub 2021 Jul 2.

Structural Biology and Bioinformatics, Department of Biochemistry, University of Melbourne, Parkville 3052, Victoria, Australia.

The development of new, effective, and safe drugs to treat cancer remains a challenging and time-consuming task due to limited hit rates, restraining subsequent development efforts. Despite the impressive progress of quantitative structure-activity relationship and machine learning-based models that have been developed to predict molecule pharmacodynamics and bioactivity, they have had mixed success at identifying compounds with anticancer properties against multiple cell lines. Here, we have developed a novel predictive tool, pdCSM-cancer, which uses a graph-based signature representation of the chemical structure of a small molecule in order to accurately predict molecules likely to be active against one or multiple cancer cell lines. Read More

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[Determination of the binding of natural products to the human c-myb oncogene promoter G-quadruplex DNA by capillary electrophoresis and electrospray ionization mass spectrometry].

Se Pu 2020 Sep;38(9):1069-1077

Department of Chemistry, University of British Columbia, Vancouver, BC V6T 1Z1, Canada.

The relationship between a drug and its target directly affects its pharmacology and efficacy. Drug-target binding ability and binding stoichiometry are essential characterization data in pharmaceutical research. The c-myb proto-oncogene encodes a crucial transcription factor that is involved in proliferation, differentiation, and maturation during hematopoiesis. Read More

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September 2020

[Recent advances in chemical derivatization-based chromatography-mass spectrometry methods for analysis of aldehyde biomarkers].

Se Pu 2021 Aug;39(8):845-854

College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.

Human exposure to chemical pollutants in the environment can cause a variety of diseases, including cancer, diabetes, cardiovascular disease, and neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, etc.). Exogenous and environmental pollutant exposure-induced endogenous aldehydes are highly reactive electrophilic compounds that can form covalently modified products with a variety of important biological molecules in the human body, thus inducing toxic effects. Read More

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Anti-angiogenesis in cancer therapeutics: the magic bullet.

J Egypt Natl Canc Inst 2021 Jul 2;33(1):15. Epub 2021 Jul 2.

Institute of Cardiovascular Science, University College London, London, UK.

Background: Angiogenesis is the formation of new vascular networks from preexisting ones through the migration and proliferation of differentiated endothelial cells. Available evidence suggests that while antiangiogenic therapy could inhibit tumour growth, the response to these agents is not sustained. The aim of this paper was to review the evidence for anti-angiogenic therapy in cancer therapeutics and the mechanisms and management of tumour resistance to antiangiogenic agents. Read More

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Enantioenriched Positive Allosteric Modulators Display Distinct Pharmacology at the Dopamine D Receptor.

Molecules 2021 Jun 22;26(13). Epub 2021 Jun 22.

Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia.

(1) Background: Two first-in-class racemic dopamine D receptor (DR) positive allosteric modulator (PAM) chemotypes ( and ) were identified from a high-throughput screen. In particular, due to its selectivity for the DR and reported lack of intrinsic activity, compound shows promise as a starting point toward the development of small molecule allosteric modulators to ameliorate the cognitive deficits associated with some neuropsychiatric disease states; (2) Methods: Herein, we describe the enantioenrichment of optical isomers of using chiral auxiliaries derived from ()- and ()-3-hydroxy-4,4-dimethyldihydrofuran-2(3)-one (d- and l-pantolactone, respectively); (3) Results: We confirm both the racemate and enantiomers of are active and selective for the DR, but that the respective stereoisomers show a significant difference in their affinity and magnitude of positive allosteric cooperativity with dopamine; (4) Conclusions: These data warrant further investigation of asymmetric syntheses of optically pure analogues of for the development of DR PAMs with superior allosteric properties. Read More

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A Novel Protein-Protein Interaction between RSK3 and IκBα and a New Binding Inhibitor That Suppresses Breast Cancer Tumorigenesis.

Cancers (Basel) 2021 Jun 14;13(12). Epub 2021 Jun 14.

Research Center for Bioconvergence Analysis, Korea Basic Science Institute (KBSI), Cheongju 28119, Korea.

Multiple cancer-related biological processes are mediated by protein-protein interactions (PPIs). Through interactions with a variety of factors, members of the ribosomal S6 kinase (RSK) family play roles in cell cycle progression and cell proliferation. In particular, RSK3 contributes to cancer viability, but the underlying mechanisms remain unknown. Read More

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Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp14 RNA cap methyltransferase.

Biochem J 2021 07;478(13):2481-2497

Chromosome Replication Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.

The COVID-19 pandemic has presented itself as one of the most critical public health challenges of the century, with SARS-CoV-2 being the third member of the Coronaviridae family to cause a fatal disease in humans. There is currently only one antiviral compound, remdesivir, that can be used for the treatment of COVID-19. To identify additional potential therapeutics, we investigated the enzymatic proteins encoded in the SARS-CoV-2 genome. Read More

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Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp14/nsp10 exoribonuclease.

Biochem J 2021 07;478(13):2445-2464

Chromosome Replication Laboratory, the Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.

SARS-CoV-2 is a coronavirus that emerged in 2019 and rapidly spread across the world causing a deadly pandemic with tremendous social and economic costs. Healthcare systems worldwide are under great pressure, and there is an urgent need for effective antiviral treatments. The only currently approved antiviral treatment for COVID-19 is remdesivir, an inhibitor of viral genome replication. Read More

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