PubChem: a public information system for analyzing bioactivities of small molecules

Wang, Yanli; Xiao, Jewen; Önal-Süzek, Tuğba; Zhang, Jian; Wang, Jiyao; Bryant, Stephen H.

doi:10.1093/nar/gkp456

Cited by 1,193 publications

(890 citation statements)

References 13 publications

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“…25 BRD2879 was inactive in all 40 screening assays for which results are available on PubChem, including a screen for inhibitors of KDM4C, which like IDH1 uses α-KG as a cofactor. Overall, the potency of BRD2879, its encouraging preliminary SAR, and its lack of activity in other screens led us to prioritize this scaffold for follow-up experiments.…”

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

Discovery of 8-Membered Ring Sulfonamides as Inhibitors of Oncogenic Mutant Isocitrate Dehydrogenase 1

Law

Stark

Liu

et al. 2016

ACS Med. Chem. Lett.

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Evidence suggests that specific mutations of isocitrate dehydrogenases 1 and 2 (IDH1/2) are critical for the initiation and maintenance of certain tumor types and that inhibiting these mutant enzymes with small molecules may be therapeutically beneficial. In order to discover mutant alleleselective IDH1 inhibitors with chemical features distinct from existing probes, we screened a collection of small molecules derived from diversity-oriented synthesis. The assay identified compounds that inhibit the IDH1-R132H mutant allele commonly found in glioma. Here, we report the discovery of a potent (IC 50 = 50 nM) series of IDH1-R132H inhibitors having 8-membered ring sulfonamides as exemplified by the compound BRD2879. The inhibitors suppress (R)-2-hydroxyglutarate production in cells without apparent toxicity. Although the solubility and pharmacokinetic properties of the specific inhibitor BRD2879 prevent its use in vivo, the scaffold presents a validated starting point for the synthesis of future IDH1-R132H inhibitors having improved pharmacological properties. KEYWORDS: BRD2879, isocitrate dehydrogenase, 2-hydroxyglutarate, glioma, AML, cancer, diversity-oriented synthesis, high-throughput screening, allele-selective probe, small-molecule probe S ystematic efforts to characterize the genomes of patient tumors are revealing the genomic alterations that cause and maintain different cancers. Somatic mutations in the genes encoding the isocitrate dehydrogenases IDH1 and IDH2 have been found in >70% of grade II−III gliomas and secondary glioblastomas, 1,2 ∼17% of acute myeloid leukemias (AML), 3,4 ∼56% of central and periosteal chondrosarcoma, 5 and sporadically in other tumor types. Mutations are nearly always heterozygous and occur frequently at codons IDH1-R132, IDH2-R172, or IDH2-R140. IDH enzymes normally catalyze the interconversion of isocitrate and α-ketoglutarate (α-KG), but these mutations unmask an otherwise cryptic NADPH-dependent ketoreductase activity, allowing the enzyme to reduce α-KG to (R)-2-hydroxyglutarate (R-2HG). 3,6 As a result, R-2HG levels are elevated >50-fold in samples from patients with IDH mutations. 3 The pathogenesis of IDH mutant tumors is thought to center on the ability of R-2HG to act as an "oncometabolite". Due to its structural similarity to α-KG, R-2HG competitively inhibits several α-KG-dependent dioxygenases when present at the high concentrations observed in IDH mutant tumors. In particular, R-2HG impairs DNA demethylation through inhibition of TET2, 7 impairs histone demethylation through inhibition of various lysine demethylases, 8,9 and modulates hypoxic stress response through activation of EGLN1. 10 These molecular changes are thought to cause the enhanced proliferation and impaired differentiation observed in IDH mutant tumors. The mutual exclusivity of IDH and TET2 mutations in AML tumors 7 and the ability of exogenous R-2HG to induce leukemogenesis in blood cells 11 further implicate R-2HG as a critical mediator in how mutant IDH contributes to AML. In IDH1 muta...

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Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

Discovery of 8-Membered Ring Sulfonamides as Inhibitors of Oncogenic Mutant Isocitrate Dehydrogenase 1

Law

Stark

Liu

et al. 2016

ACS Med. Chem. Lett.

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“…This selection would be facilitated if a simple overview of the known chemical space was available [9]. Herein we report an analysis and visualisation of the 4.5 million fragment-sized molecules currently reported in the public access database PubChem [10] using the MQN-system.…”

Section: Introductionmentioning

confidence: 99%

Visualisation of the chemical space of fragments, lead-like and drug-like molecules in PubChem

Deursen

Blum

Reymond

2011

J Comput Aided Mol Des

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The 4.5 million organic molecules with up to 20 non-hydrogen atoms in PubChem were analyzed using the MQN-system, which consists in 42 integer value descriptors of molecular structure. The 42-dimensional MQN-space was visualised by principal component analysis and representation of the (PC1, PC2), (PC1, PC3) and (PC2, PC3) planes. The molecules were organized according to ring count (PC1, 38% of variance), the molecular size (PC2, 25% of variance), and the H-bond acceptor count (PC3, 12% of variance). Compounds following Lipinski's bioavailability, Oprea's lead-likeness and Congreve's fragment-likeness criteria formed separated groups in MQN-space visible in the (PC2, PC3) plane. MQN-similarity searches of the 4.5 million molecules (see the browser available at www.gdb.unibe.ch) gave significant enrichment factors for recovering groups of fragment-sized bioactive compounds related to ten different biological targets taken from Chembl, allowing leadhopping relationships not seen with substructure fingerprint similarity searches. The diversity of different compound series was analyzed by MQN-distance histograms.

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“…The lower layer was a drug structural similarity network that was also a complete graph. The chemical structures (SDF files) of the drugs were downloaded from the PubChem database (Wang et al ., 2009). Taking the SDF files as input, drug properties served as numerical molecular descriptors were obtained using the PaDEL‐Descriptor with default settings (Yap, 2011).…”

Section: Methodsmentioning

confidence: 99%

Inferences of individual drug responses across diverse cancer types using a novel competing endogenous RNA network

Zhang

Zhou

et al. 2018

Molecular Oncology

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Differences in individual drug responses are an obstacle to progression in cancer treatment, and predicting responses would help to plan treatment. The accumulation of cancer molecular profiling and drug response data provides opportunities and challenges to identify novel molecular signatures and mechanisms of tumor responsiveness to drugs. This study evaluated drug responses with a competing endogenous RNA (ceRNA) system that depended on competition between diverse RNA species. We identified drug response‐related ceRNA (DRCEs) by combining the sequence and expression data of long noncoding RNA (lncRNA), microRNA (miRNA), and messenger RNA (mRNA), and the survival data of cancer patients treated with drugs. We constructed a patient–drug two‐layer integrated network and used a linear weighting method to predict individual drug responses. DRCEs were found to be significantly enriched in known cancer and drug‐associated data resources, involved in biological processes known to mediate drug responses, and correlated to drug activity in cancer cell lines. The dysregulation of DRCE expression influenced drug response‐associated functions and pathways, suggesting DRCEs as potential therapeutic targets affecting drug responses. A further case study in breast invasive carcinoma (BRCA) found that DRCE expression was consistent with the drug response pattern and the aberrant expression of the two NEAT1‐related DRCEs may lead to poor response to tamoxifen therapy for patients with TP53 mutations. In summary, this study provides a framework for ceRNA‐based evaluation of clinical drug responses across multiple cancer types. Understanding the underlying molecular mechanisms of drug responses will allow improved response to chemotherapy and outcomes of cancer treatment.

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PubChem: a public information system for analyzing bioactivities of small molecules

Cited by 1,193 publications

References 13 publications

Discovery of 8-Membered Ring Sulfonamides as Inhibitors of Oncogenic Mutant Isocitrate Dehydrogenase 1

Discovery of 8-Membered Ring Sulfonamides as Inhibitors of Oncogenic Mutant Isocitrate Dehydrogenase 1

Visualisation of the chemical space of fragments, lead-like and drug-like molecules in PubChem

Inferences of individual drug responses across diverse cancer types using a novel competing endogenous RNA network

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