Entries by webadmin

Sipthorp et al., ” Visualization of Endogenous ERK1/2 in Cells with a Bioorthogonal Covalent Probe.” Bioconjugate Chemistry, (JUN 2017) Vol. 28, No. 6, pp. 1677-1683; DOI: 10.1021/acs.bioconjchem.7b0015

Abstract The RAS–RAF–MEK–ERK pathway has been intensively studied in oncology, with RAS known to be mutated in ∼30% of all human cancers. The recent emergence of ERK1/2 inhibitors and their ongoing clinical investigation demands a better understanding of ERK1/2 behavior following small-molecule inhibition. Although fluorescent fusion proteins and fluorescent antibodies are well-established methods of visualizing […]

Lebraud et al., “Protein degradation: a validated therapeutic strategy with exciting prospects.” Essays in Biochemistry (2017) 61 517–527; DOI: 10.1042/EBC20170030

Abstract In a time of unprecedented challenges in developing potent, selective and well-tolerated protein inhibitors as therapeutics, drug hunters are increasingly seeking alternative modalities to modulate pharmacological targets. Selective inhibitors are achievable for only a fraction of the proteome, and are not guaranteed to elicit the desired response in patients, especially when pursuing targets identified […]

Price et al., “Fragment-based drug discovery and its application to challenging drug targets.” Essays in Biochemistry (2017) 61 475–484; DOI: 10.1042/EBC20170029

Abstract Fragment-based drug discovery (FBDD) is a technique for identifying low molecular weight chemical starting points for drug discovery. Since its inception 20 years ago, FBDD has grown in popularity to the point where it is now an established technique in industry and academia. The approach involves the biophysical screening of proteins against collections of […]

Wright et al., “Engineering and purification of a thermostable, high-yield, variant of PfCRT, the Plasmodium falciparum chloroquine resistance transporter.” Protein Expression and Purification 141 (2018) 7-18; DOI: 10.1016/j.pep.2017.08.005

Abstract Historically chloroquine was used to treat the most deadly form of malaria, caused by the parasite Plasmodium falciparum. The selective pressure of chloroquine therapy led to the rapid emergence of chloroquine resistant parasites. Resistance has been attributed to the Plasmodium falciparumChloroquine Resistance Transporter (PfCRT), an integral membrane protein of unknown structure. A PfCRT structure would provide new insights into how the […]

Ward et al., “ASTX660, a novel non-peptidomimetic antagonist of cIAP1/2 and XIAP, potently induces TNF-α dependent apoptosis in cancer cell lines and inhibits tumor growth.” Molecular Cancer Therapeutics 2018 pre-publication; DOI: 10.1158/1535-7163.MCT-17-0848

Abstract Because of their roles in the evasion of apoptosis, inhibitor of apoptosis proteins (IAP) are considered attractive targets for anticancer therapy. Antagonists of these proteins have the potential to switch prosurvival signaling pathways in cancer cells toward cell death. Various SMAC-peptidomimetics with inherent cIAP selectivity have been tested clinically and demonstrated minimal single-agent efficacy. […]

Johnson et al., “Fragment-to-Lead Medicinal Chemistry Publications in 2016.” J. Med. Chem. 2018, 61, 1774−1784; ; DOI: 10.1021/acs.jmedchem.7b01298

Abstract The popularity of fragment-based drug discovery (FBDD) is demonstrated by the number of recent successful fragment-to-lead (F2L) publications. This Miniperspective provides a tabulated summary of the F2L literature published in the year 2016, along with discussion of general trends. It uses the same format as our summary of the 2015 literature and is intended […]

Lebraud et al., “A highly potent clickable probe for cellular imaging of MDM2 and assessing dynamic responses to MDM2-p53 inhibition.” Bioconjugate Chemistry 2018 (ahead of print), ; DOI: 10.1021/acs.bioconjchem.8b00315

Abstract MDM2 is a key negative regulator of the p53 tumor suppressor. Direct binding of MDM2 to p53 represses the protein’s transcriptional activity and induces its polyubiquitination, targeting it for degradation by the proteasome. Consequently, small molecule inhibitors that antagonize MDM2-p53 binding, such as RG7388, have progressed into clinical development aiming to reactivate p53 function […]

Heightman et al., “Fragment-Based Discovery of a Potent, Orally Bioavailable Inhibitor That Modulates the Phosphorylation and Catalytic Activity of ERK1/2.” J. Med. Chem. 2018 61, 11, 4978-4992, ; DOI: 10.1021/acs.jmedchem.8b00421

Abstract Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signaling through ERK1/2. Here, we describe the fragment-based generation of ERK1/2 inhibitors that block catalytic phosphorylation of downstream substrates […]

Agni Gavriilidou et al., “Advancing Life Sciences R&D 2018 Online, Application of Native ESI-MS to Characterize Interactions between Compounds Derived from Fragment-Based Discovery Campaigns and Two Pharmaceutically Relevant Proteins.” SLAS Discovery, DOI: 10.1177/2472555218775921

Abstract Native electrospray ionization mass spectrometry (ESI-MS) was applied to analyze the binding of compounds generated during fragment-based drug discovery (FBDD) campaigns against two functionally distinct proteins, the X-linked inhibitor of apoptosis protein (XIAP) and cyclin-dependent kinase 2 (CDK2). Compounds of different molecular weights and a wide range of binding affinities obtained from the hits […]

2018: ASTX660, a Novel Non-peptidomimetic Antagonist of cIAP1/2 and XIAP, Potently Induces TNFα-Dependent Apoptosis in Cancer Cell Lines and Inhibits Tumor Growth.

Abstract Because of their roles in the evasion of apoptosis, inhibitor of apoptosis proteins (IAP) are considered attractive targets for anticancer therapy. Antagonists of these proteins have the potential to switch prosurvival signaling pathways in cancer cells toward cell death. Various SMAC-peptidomimetics with inherent cIAP selectivity have been tested clinically and demonstrated minimal single-agent efficacy. […]