Inhibitors of Human Divalent Metal Transporters DMT1 (SLC11A2) and ZIP8 (SLC39A8) from a GDB-17 Fragment Library.

Solute carrier proteins (SLCs) are membrane proteins controlling fluxes across biological membranes and represent an emerging class of drug targets. Here we searched for inhibitors of divalent metal transporters in a library of 1,676 commercially available 3D-shaped fragment-like molecules from the generated database GDB-17, which lists all possible organic molecules up to 17 atoms of C, N, O, S and halogen following simple criteria for chemical stability and synthetic feasibility. While screening against DMT1 (SLC11A2), an iron transporter associated with hemochromatosis and for which only very few inhibitors are known, only yielded two weak inhibitors, our approach led to the discovery of the first inhibitor of ZIP8 (SLC39A8), a zinc transporter associated with manganese homeostasis and osteoarthritis but with no previously reported pharmacology, demonstrating that this target is druggable.

Pyrazolyl-pyrimidones inhibit the function of human solute carrier protein SLC11A2 (hDMT1) by metal chelation.

Solute carrier proteins (SLCs) control fluxes of ions and molecules across biological membranes and represent an emerging class of drug targets. SLC11A2 (hDMT1) mediates intestinal iron uptake and its inhibition might be used to treat iron overload diseases such as hereditary hemochromatosis. Here we report a micromolar (IC = 1.

The Generated Databases (GDBs) as a Source of 3D-shaped Building Blocks for Use in Medicinal Chemistry and Drug Discovery.

Drug discovery is in constant need of new molecules to develop drugs addressing unmet medical needs. To assess the chemical space available for drug design, our group investigates the generated databases (GDBs) listing all possible organic molecules up to a defined size, the largest of which is GDB-17 featuring 166.4 billion molecules up to 17 non-hydrogen atoms.

ChEMBL-Likeness Score and Database GDBChEMBL.

The generated database GDB17 enumerates 166.4 billion molecules up to 17 atoms of C, N, O, S and halogens following simple rules of chemical stability and synthetic feasibility. However, most molecules in GDB17 are too complex to be considered for chemical synthesis.

Transcriptional repression of the prosurvival endoplasmic reticulum chaperone GRP78/BIP by E2F1.

The endoplasmic reticulum chaperone GRP78/BIP plays a central role in the prosurvival machinery, and its enhanced expression has been implicated in drug resistance, carcinogenesis, and metastasis. E2F1, as part of an antitumor safeguard mechanism, promotes apoptosis regardless of functional p53. Using cells that are defective in p53, we show that E2F1 represses GRP78/BIP at the transcriptional level, and this requires its DNA binding domain.

Molecular mechanism of p73-mediated regulation of hepatitis B virus core promoter/enhancer II: implications for hepatocarcinogenesis.

Hepatitis B virus (HBV) is a causative agent of chronic hepatitis and hepatocellular carcinoma. Recent findings demonstrating p73 and specifically N-terminally truncated p73 (DeltaTAp73) accumulation in hepatocellular carcinoma suggest that p73 plays a role in the malignant phenotype. Here, we investigated the mechanism of HBV pregenomic core promoter/enhancer II (cp/EII) regulation by full-length TAp73 and its oncogenic counterpart DeltaTAp73.

DNp73 a matter of cancer: mechanisms and clinical implications.

The p53 family proteins carry on a wide spectrum of biological functions from differentiation, cell cycle arrest, apoptosis, and chemosensitivity of tumors. NH2-terminally truncated p73 (referred to as DNp73) acts as a potent inhibitor of all these tumor suppressor properties, implying that it has oncogenic functions in human tumorigenesis. This was favored by the observation that high DNp73 expression levels in a variety of cancers are associated with adverse clinico-pathological characteristics and the response failure to chemotherapy.

Autonomous growth and hepatocarcinogenesis in transgenic mice expressing the p53 family inhibitor DNp73.

p53 family proteins carry on a wide spectrum of biological functions from differentiation, cell cycle arrest, apoptosis and chemosensitivity of tumors. Conversely, N-terminally truncated p73 (DNp73) functions as a potent inhibitor of all these tumor suppressor properties, implicating its participation in malignant transformation and oncogenesis. Several reports indicated considerable up-regulation of DNp73 in hepatocellular carcinoma (HCC) that correlates with reduced survival of patients, but little is known about the functional significance of DNp73 to tumorigenesis in vivo due to the lack of an appropriate model.

Clinical features and neuropathology of autosomal dominant spinocerebellar ataxia (SCA17).

Autosomal dominant spinocerebellar ataxias (SCAs) are a group of neurodegenerative disorders clinically characterized by late-onset ataxia and variable other manifestations. Genetically and clinically, SCA is highly heterogeneous. Recently, CAG repeat expansions in the gene encoding TATA-binding protein (TBP) have been found in a new form of SCA, which has been designated SCA17.