A5037178716- Epigenetics and DNA Methylation
- RNA modifications and cancer
- DNA Repair Mechanisms
- PARP inhibition in cancer therapy
- RNA Research and Splicing
- Cancer-related gene regulation
- Malaria Research and Control
- Computational Drug Discovery Methods
- RNA and protein synthesis mechanisms
- MicroRNA in disease regulation
- Cancer therapeutics and mechanisms
- CRISPR and Genetic Engineering
- Mosquito-borne diseases and control
- Genetics, Aging, and Longevity in Model Organisms
- Cancer-related Molecular Pathways
- Genomics and Chromatin Dynamics
- BRCA gene mutations in cancer
- Vascular Tumors and Angiosarcomas
- Neuroblastoma Research and Treatments
- Plant Virus Research Studies
- Polyamine Metabolism and Applications
- Pharmacological Receptor Mechanisms and Effects
- Histone Deacetylase Inhibitors Research
- Cell death mechanisms and regulation
- Molecular Biology Techniques and Applications
National Center for Advancing Translational Sciences
2016-2025
National Institutes of Health
2012-2025
Xi’an Jiaotong-Liverpool University
2022
National Human Genome Research Institute
2011
Royal Children's Hospital
2005
A major cause of the paucity new starting points for drug discovery is lack interaction between academia and industry. Much global resource in biology present universities, whereas focus medicinal chemistry still largely within Open source discovery, with sharing information, clearly a first step towards overcoming this gap. But interface could especially be bridged through scale-up open physical compounds, which would accelerate finding discovery. The Medicines Malaria Venture Box...
Malaria remains a devastating disease largely because of widespread drug resistance. New drugs and better understanding the mechanisms action resistance are essential for fulfilling promise eradicating malaria. Using high-throughput chemical screening genome-wide association analysis, we identified 32 highly active compounds genetic loci associated with differential phenotypes (DCPs), defined as greater than or equal to fivefold differences in half-maximum inhibitor concentration (IC(50))...
The chromatin-associated protein WDR5 is a promising target for pharmacological inhibition in cancer. Drug discovery efforts center on the blockade of "WIN site" WDR5, well-defined pocket that amenable to small molecule inhibition. Various cancer contexts have been proposed be targets WIN site inhibitors, but lack understanding genes and primary effects inhibitors hampers their utility. Here, by potent we demonstrate links chromatin at cohort loci, including specific subset ribosome genes....
Significance Schlafen-11 (SLFN11) inactivation leads to chemoresistance of a broad range DNA-damaging agents. We uncover an expanded Ataxia Telangiectasia- and Rad3-related (ATR)-mediated signaling network that overcomes by unbiased genome-wide RNAi screen in SLFN11 -knockout cells is validated with clinically developing ATR/CHK1 inhibitors. ATR inhibition induces CDT1 phosphorylation, leading mitotic catastrophe cell death SLFN11-deficient cells. identify key role for degradation binding...
Abstract PARP inhibitor (PARPi)–resistant BRCA-mutant (BRCAm) high-grade serous ovarian cancer (HGSOC) represents a new clinical challenge with unmet therapeutic needs. Here, we performed quantitative high-throughput drug combination screen that identified the of an ATR (ATRi) and AKT (AKTi) as effective treatment strategy for both PARPi-sensitive PARPi-resistant BRCAm HGSOC. The ATRi AKTi induced DNA damage R loop–mediated replication stress (RS). Mechanistically, kinase domain AKT1...
The nonsense-mediated mRNA decay (NMD) pathway detects aberrant transcripts containing premature termination codons (PTCs) and regulates expression of 5–10% non-aberrant human mRNAs. To date, most proteins involved in NMD have been identified by genetic screens model organisms; however, the increased complexity gene regulation cells suggests that additional may participate pathway. identify required for NMD, we performed a genome-wide RNAi screen against >21,000 genes. Canonical members...
Dysbiosis of gut microbiota plays a pivotal role in vascular dysfunction and microbial diversity was reported to be inversely correlated with arterial stiffness. However, the causal progression stiffness specific species along molecular mechanisms underlying this change remain largely unknown.Participants elevated normal controls free medication were matched for age sex. The composition metabolic capacities between 2 groups compared integration metagenomics metabolomics. Subsequently, Ang II...
Abstract The centromeric histone H3 variant CENP-A is overexpressed in many cancers. mislocalization of to noncentromeric regions contributes chromosomal instability (CIN), a hallmark cancer. However, pathways that promote or prevent remain poorly defined. Here, we performed genome-wide RNAi screen for regulators localization which identified DNAJC9, J-domain protein implicated H3–H4 folding, as factor restricting mislocalization. Cells lacking DNAJC9 exhibit throughout the genome, and CIN...
Abstract Schlafen11 (SLFN11) inactivation occurs in approximately 50% of cancer cell lines and a large fraction patient tumor samples, which leads to chemoresistance. Therefore, new therapeutic approaches are needed target SLFN11-deficient cancers. To that effect, we conducted drug screen with the NCATS mechanistic library 1,978 compounds isogenic SLFN11-knockout (KO) wild-type (WT) leukemia lines. Here report TAK-243, first-in-class ubiquitin activating enzyme UBA1 inhibitor clinical...
Poly(ADP-ribose) polymerase inhibitors (PARPis) have changed the treatment paradigm in breast cancer gene ( BRCA )–mutant high-grade serous ovarian carcinoma (HGSC). However, most patients eventually develop resistance to PARPis, highlighting an unmet need for improved therapeutic strategies. Using high-throughput drug screens, we identified ataxia telangiectasia and rad3-related protein/checkpoint kinase 1 (CHK1) pathway as cytotoxic further validated activity of CHK1 inhibitor (CHK1i)...
Here, we describe the discovery of a novel antimalarial agent using phenotypic screening Plasmodium falciparum asexual blood-stage parasites. Screening compound collection created diversity-oriented synthesis (DOS) led to initial hit. Structure–activity relationships guided compounds having improved potency and water solubility, yielding subnanomolar inhibitor parasite growth. Optimized 27 has an excellent off-target activity profile in erythrocyte lysis HepG2 assays is stable human plasma....
In an effort to expand the stereochemical and structural complexity of chemical libraries used in drug discovery, Center for Chemical Methodology Library Development at Boston University has established infrastructure translate methodologies accessing diverse chemotypes into arrayed biological evaluation. a collaborative effort, NIH Genomics determined IC 50 ’s Plasmodium falciparum viability each 2,070 members CMLD-BU compound collection using quantitative high-throughput screening across...
Abstract Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer. Most MCCs contain polyomavirus (virus-positive MCC; VP-MCC), and the remaining are virus-negative (VN-MCC). Immune checkpoint inhibitors first-line treatment for metastatic MCC, but durable responses achieved in less than 50% of patients. To identify new treatments, we screen ~4,000 compounds their ability to reduce MCC viability demonstrate that VP-MCC VN-MCC exhibit distinct response profiles. Aurora kinase selectively...
Abstract Nicotinamide N-methyltransferase (NNMT) has emerged as a cancer therapeutic target master metabolic regulator that catalyzes the differentiation of normal fibroblasts to associated (CAFs) in stromal tissue surrounding various tumors, most notably ovarian carcinomas. NNMT activity depletes S-adenosyl methionine (SAM) reducing histone methylation. This change epigenome results changes interstitial tumor space which turn promotes growth and metastasis We will present development novel...
Abstract Gastro-enteropancreatic neuroendocrine neoplasms (GEP-NENs) are a diverse family of tumors which can originate throughout the gastrointestinal tract. Despite designation as rare cancer, incidence GEP-NENs has increased over last few decades. There been difficulty in developing new therapies due to lack targetable mutations present these tumors. One potential target is somatostatin receptor 2 (SSTR2), expressed many cancers. Somatostatin analogues and peptide-targeted radiotherapies...
Chromosomal instability (CIN), a major hallmark of cancer, can be driven by defects in the integrity centromere or kinetochore structure. Coordinated control phosphorylation and dephosphorylation activities during cell division is critical to ensure chromosomal stability. Overexpression centromeric histone H3 variant CENP-A observed many cancers, its mislocalization noncentromeric regions promotes CIN. We identified protein phosphatase 1 (PP1) nuclear targeting subunit (PNUTS) as top...
[<i>S</i>-<i>methyl</i>-<sup>11</sup>C](±)-7-methoxy-3-(4-(4-(methylthio)phenyl)butyl)-2,3,4,5-tetrahydro-1<i>H</i>-benzo[<i>d</i>]azepin-1-ol (<sup>11</sup>C-NR2B-SMe) and its enantiomers were synthesized as candidates for imaging the NR2B subunit within <i>N</i>-methyl-d-aspartate receptor with PET. <b>Methods:</b> Brains scanned PET 90 min after intravenous injection of one candidate radioligands into rats. To detect any NR2B-specific binding radioligand in brain, various preblocking or...
Parasitic diseases continue to have a devastating impact on human populations worldwide. Lack of effective treatments, the high cost existing ones, and frequent emergence resistance these agents provide strong argument for development novel therapies. Here we report results hybrid approach designed obtain dual acting molecule that would demonstrate activity against variety parasitic targets. The antimalarial drug amodiaquine has been covalently joined with nitric oxide-releasing furoxan...
Methyltransferases (MTases) play diverse roles in cellular processes. Aberrant methylation levels have been implicated many diseases, indicating the need for identification and development of small molecule inhibitors each MTase. Specific can serve as probes to investigate function validate therapeutic potential respective High-throughput screening (HTS) is a powerful method identify initial hits further optimization. Here, we report fluorescence-based MTase assay compare this format with...
<div>Abstract<p>PARP inhibitor (PARPi)–resistant <i>BRCA</i>-mutant (BRCAm) high-grade serous ovarian cancer (HGSOC) represents a new clinical challenge with unmet therapeutic needs. Here, we performed quantitative high-throughput drug combination screen that identified the of an ATR (ATRi) and AKT (AKTi) as effective treatment strategy for both PARPi-sensitive PARPi-resistant BRCAm HGSOC. The ATRi AKTi induced DNA damage R loop–mediated replication stress (RS)....
Charcot-Marie-Tooth 1A (CMT1A) is the most common form of hereditary peripheral neuropathies, characterized by genetic duplication critical myelin gene Peripheral Myelin Protein 22 (PMP22). PMP22 overexpression results in abnormal Schwann cell differentiation, leading to axonal loss and muscle wasting. Since regulation expression a major target therapeutic discovery for CMT1A, we sought establish unbiased approaches that allow identification agents this disease. Using genome editing,...