Ya-Qin Zhang

National Institutes of Health | NIH

Ewing sarcoma is a highly aggressive solid malignancy affecting children and young adults. Ewing sarcoma is driven primarily by EWSR1::FLI1, a fusion oncoprotein that has been notoriously difficult to target with traditional pharmacologic agents. There are numerous examples of preclinical promising combinations of small molecules that are never tes...

Cyclin-dependent kinases 4 and 6 (CDK4/6) play a pivotal role in cell cycle and cancer development. Targeting CDK4/6 has demonstrated promising effects against breast cancer. However, resistance to CDK4/6 inhibitors (CDK4/6i), such as palbociclib, remains a substantial challenge in clinical settings. Using high-throughput combinatorial drug screeni...

As part of the NIH Helping to End Addiction Long-term (HEAL) Initiative, the National Center for Advancing Translational Sciences (NCATS) is dedicated to the development of new pharmacological tools and investigational drugs for managing and treating pain, as well as the prevention and treatment of opioid misuse and addiction. In line with these ob...

Cyclin-dependent kinases 4 and 6 (CDK4/6) play a pivotal role in cell cycle and cancer development. Targeting CDK4/6 has demonstrated promising effects against breast cancer. However, resistance to CDK4/6 inhibitors (CDK4/6i), such as palbociclib, remains a substantial challenge in clinical settings. Using high-throughput combinatorial drug screeni...

Background: Anaplastic thyroid cancer (ATC) is uniformly lethal. BRAFV600E mutation is present in up to 45% of patients with ATC. Targeted therapy with combined BRAF and MEK inhibition in BRAFV600E-mutant ATC can be effective, but acquired resistance is common because this combination targets the same pathway. Drug matrix screening, in BRAFV600E A...

Recent Alzheimer's research has shown increasing interest in the caspase-2 (Casp2) enzyme. However, the available Casp2 inhibitors, which have been pentapeptides or peptidomimetics, face challenges for use as CNS drugs. In this study, we successfully screened a 1920-compound chloroacetamide-based, electrophilic fragment library from Enamine. Our tw...

Ewing sarcoma is the second most common pediatric bone cancer in children and young adults. The standard of care therapy consists of chemotherapy, surgery, and radiation. Despite therapeutic advances, metastatic and relapsed Ewing sarcoma have poor outcomes. This is partially because transcription factors, such as the Ewing sarcoma oncoprotein EWS-...

Adrenocortical cancer (ACC) is a rare and aggressive cancer (0.5-2 cases/million/year) with poor 5-year survival. Most patients inevitably succumb to widespread metastasis due to a lack of effective systemic treatment; therefore, it is critically important to identify new therapies for clinical trials. In this direction, we identified a potent syne...

Purpose: Anaplastic thyroid cancer (ATC) is one of the most aggressive human cancers, with a median survival time of 6 months and with no current curative treatment. We have used quantitative high-throughput screening (qHTS) of clinically approved or investigational agents to identify candidate compounds for ATC therapy. As monotherapy for most can...

Adrenocortical cancer (ACC) is a rare and aggressive cancer (0.5-2 cases/ million/ year) with a poor 5-year survival (<40%). Most patients inevitably succumb to the wide-spread metastasis because of the lack of effective systemic treatment options or to complications from uncontrolled hypercortisolism. Therefore, it is critically important to ident...

Background Adrenocortical cancer (ACC) is a rare and aggressive cancer with dismal 5-year survival due to a lack of effective treatments. We aimed to identify a new effective combination of drugs and investigated their synergistic efficacy in ACC preclinical models. Methods A quantitative high-throughput drug screening of 4,991 compounds was perfo...

Background Adrenocortical cancer (ACC) is a rare and aggressive cancer with dismal 5-year survival due to a lack of effective treatments. We aimed to identify a new effective combination of drugs and investigated their synergistic efficacy in ACC preclinical models. Methods A quantitative high-throughput drug screening of 4,991 compounds was perfo...

Despite the potency of most first-line anti-cancer drugs, nonadherence to these drug regimens remains high and is attributable to the prevalence of "off-target" drug effects that result in serious adverse events (SAEs) like hair loss, nausea, vomiting, and diarrhea. Some anti-cancer drugs are converted by liver uridine 5'-diphospho-glucuronosyltran...

Classic galactosemia is a rare disease caused by inherited deficiency of galactose-1 phosphate uridylyltransferase (GALT). Accumulation of galactose-1 phosphate (gal-1P) is thought to be the major cause of the chronic complications associated with this disease, which currently has no treatment. Inhibiting galactokinase (GALK1), the enzyme that gene...

Dystonias are a group of chronic movement–disabling disorders for which highly effective oral medications or disease-modifying therapies are lacking. The most effective treatments require invasive procedures such as deep brain stimulation. In this study, we used a high-throughput assay based on a monogenic form of dystonia, DYT1 (DYT-TOR1A), to scr...

Major advances have been made to improve the sensitivity of mass analyzers, spectral quality, and speed of data processing enabling more comprehensive proteome discovery and quantitation. While focus has recently begun shifting toward robust proteomics sample preparation efforts, a high-throughput proteomics sample preparation is still lacking. We...

Classic Galactosemia is a potentially lethal autosomal recessive metabolic disorder caused by deficient galactose-1-phosphate uridyltransferase (GALT) that results in the buildup of galactose-1-phosphate (gal-1-p) in cells. Galactokinase (GALK1) is the enzyme responsible for converting galactose into gal-1-p. A pharmacological inhibitor of GALK1 is...

Natural products and their derivatives continue to be wellsprings of nascent therapeutic potential. However, many laboratories have limited resources for biological evaluation, leaving their previously isolated or synthesized compounds largely or completely untested. To address this issue, the Canvass library of natural products was assembled, in c...

Natural products and their derivatives continue to be wellsprings of nascent therapeutic potential. However, many laboratories have limited resources for biological evaluation, leaving their previously isolated or synthesized compounds largely or completely untested. To address this issue, the Canvass library of natural products was assembled, in c...

Natural products and their derivatives continue to be wellsprings of nascent therapeutic potential. However, many laboratories have limited resources for biological evaluation, leaving their previously isolated or synthesized compounds largely or completely untested. To address this issue, the Canvass library of natural products was assembled, in c...

Drug repurposing is an effective approach to identify active drugs with known toxicity profiles for rare cancers such as ACC. The objective of this study was to determine the anticancer activity of combination treatment for ACC from previously identified candidate agents using quantitative high-throughput screening (qHTS). In this study, we evaluat...

Hepatocellular carcinoma (HCC) accounting for roughly 90% of all primary liver neoplasms is the sixth most frequent neoplasm and the second prominent reason of tumor fatality worldwide. As regulators of diverse biological processes, long non-coding RNAs (lncRNAs) are involved in onset and development of neoplasms. With the continuous booming of wel...

Drug repurposing approaches have the potential advantage of facilitating rapid and cost-effective development of new therapies. Particularly, the repurposing of drugs with known safety profiles in children could bypass or streamline toxicity studies. We employed a phenotypic screening paradigm on a panel of well-characterized cell lines derived fro...

Transforming growth factor beta (TGF-β) promotes the pathogenesis of hepatocellular carcinoma (HCC). We evaluated the associations between TGF-β1 expression and clinicopathological parameters in HCC patients from The Cancer Genome Atlas (TCGA), as well as the prognostic power of TGF-β1 expression. Eligible studies were retrieved from several databa...

Upregulation of lncRNA H19 expression is associated with an unfavorable prognosis in some cancers. However, the prognostic value of H19 in female-specific cancers has remained uncharacterized. In this study, the prognostic power of high H19 expression in female cancer patients from the TCGA datasets was analyzed using Kaplan-Meier survival curves a...

Loss of function mutations in Kelch Like ECH Associated Protein 1 (KEAP1), or gain-of-function mutations in nuclear factor erythroid 2-related factor 2 (NRF2), are common in non-small cell lung cancer (NSCLC) and associated with therapeutic resistance. To discover novel NRF2 inhibitors for targeted therapy, we conducted a quantitative high-throughp...

Fig. S1, related to Fig. 1: Quantification of lipid storage amounts in fly cells and the activity of CT1 (THI-4), CT2 (TPE-5) and CT3 (AU-6) in Drosophila Kc167 cells.Drosophila S3 (a, b) or Kc167 (a,c) cells were incubated with increasing amounts of OA for 16 h before they were fixed and stained for nuclei/DNA using Hoechst (shown in blue) and LDs...

Supplemental Experimental Procedures.

RNA-Seq gene expression values (FPKM values) for each separate sample.

RNA-Seq gene expression values (FPKM values) per sample.

The table summarizes the results for 919 differentially expressed genes used for the clusters shown in Fig. 3a and Fig. S4c.

Details of the GO-class enrichment of the clusters shown in Fig. 3a. Table relates also to Figure S4d.

CuffDiff results indicating significance of differential gene expression between two samples.

Highlights • We identified > 600 potent small molecule inhibitors of cellular lipid storage deposition. •RNA-Seq expression profiling discriminated the activity of three lead scaffolds and guided subsequent functional studies. •We discovered a class of DGAT1 inhibitors, which is active in fly and mammalian cell lines as well as whole flies. Obesity...

Hepatitis C virus (HCV) poses a major health threat to the world. The recent development of direct-acting antivirals (DAAs) against HCV has markedly improved the response rate of HCV and reduced the side effects in comparison to the interferon-based therapy. Despite this therapeutic advance, there is still a need to develop new inhibitors that targ...

Adrenocortical carcinoma (ACC) represents one of the most resistant human cancers to systemic chemotherapy and a major clinical challenge in the field of endocrine oncology. Recent molecular characterizations of ACC suggest new opportunities for targeted therapy. The current study aimed to evaluate expression and function of TOP2A in human adrenoco...

Adrenocortical carcinoma (ACC) is a rare but aggressive malignancy with no effective therapy for patients with unresectable disease. The aim of the current study was 1) to evaluate TOP2A expression and function in human adrenocortical neoplasm and ACC cells, and 2) to determine the anticancer activity of agents which target TOP2A. TOP2A mRNA and pr...

Background Drug repurposing for cancer treatment is an emerging approach to discover clinically approved drugs that demonstrate antineoplastic effect. The effective therapeutics for patients with advanced adrenocortical carcinoma(ACC) are greatly needed. The objective of this study was to identify and validate drugs with antineoplastic effect in AC...

References. References of pharmacokinetics of 21 selected active drugs.

Table S1. Seventy-nine active compounds against NCI-H295R from quantitative high throughput screening.

Figure S1. Quantitative high-throughput screening performance assessment. Figures show low plate variation, high signal to background (S/B) ratio, and Z-factor between 0.5 to 1.0, indicating excellent assay performance.

The list of 2,816, clinically utilized, compounds used in quantitative high-throughput screening.

We measured the "druggability" of the ATP-dependent luciferase derived from the firefly Photuris pennsylvanica that was optimized using directed evolution (Ultra-Glo, Promega). Quantitative high-throughput screening (qHTS) was used to determine IC(50)s of 198899 samples against a formulation of Ultra-Glo luciferase (Kinase-Glo). We found that only...

We describe here a series of N-(quinolin-8-yl)benzenesulfonamides capable of suppressing the NFkappaB pathway identified from two high-throughput screens run at two centers of the NIH Molecular Libraries Initiative. These small molecules were confirmed in both primary and secondary assays of NFkappaB activation and expanded upon through analogue sy...

A cell-sensor assay for stabilization of IkappaBalpha was developed in the activated B cell-like diffuse large B-cell lymphoma cell line OCI-Ly3. This cell line expresses known nuclear factor kappaB (NFkappaB) target genes due to high constitutive activity of IkappaB kinase (IKK), which phosphorylates the protein IkappaBalpha leading to proteasomal...

Microtiter plate readers have evolved from photomultiplier and charged-coupled device-based readers, where a population-averaged signal is detected from each well, to microscope-based imaging systems, where cellular characteristics from individual cells are measured. For these systems, speed and ease of data analysis are inversely proportional to t...

Lipid droplets (LDs) are the universal lipid storage organelles [1, 2]. Lipids remobilized from LDs are used both for energy production via beta-oxidation or anabolic reactions, such as membrane biosynthesis [3–5]. We have previously described three probes ML206, ML219, and ML220, which were optimized from high-throughput screening hits of Drosophi...