Oh A.,Genentech |
Ho Y.-C.,FORMA Therapeutics |
Zak M.,Genentech |
Liu Y.,Pharmaron Beijing Co. |
And 6 more authors.
ChemBioChem | Year: 2014
Prolonged inhibition of nicotinamide phosphoribosyltransferase (NAMPT) is a strategy for targeting cancer metabolism. Many NAMPT inhibitors undergo NAMPT-catalyzed phosphoribosylation (pRib), a property often correlated with their cellular potency. To understand this phenomenon and facilitate drug design, we analyzed a potent cellularly active NAMPT inhibitor (GNE-617). A crystal structure of pRib-GNE-617 in complex with NAMPT protein revealed a relaxed binding mode. Consistently, the adduct formation resulted in tight binding and strong product inhibition. In contrast, a biochemically equipotent isomer of GNE-617 (GNE-643) also formed pRib adducts but displayed significantly weaker cytotoxicity. Structural analysis revealed an altered ligand conformation of GNE-643, thus suggesting weak association of the adducts with NAMPT. Our data support a model for cellularly active NAMPT inhibitors that undergo NAMPT-catalyzed phosphoribosylation to produce pRib adducts that retain efficient binding to the enzyme. Tighter and stronger: Using structural and biochemical methods, we have delineated three categories of nicotinamide phosphoribosyltransferase (NMAPT) inhibitors with various cellular activities. We found that the binding characteristics of the inhibitor adduct likely contribute to inhibitory potency in cellular environments. These methods are suitable for identifying desirable NAMPT inhibitors. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
PubMed | Genentech and Pharmaron Beijing Co.
Type: Journal Article | Journal: Bioorganic & medicinal chemistry letters | Year: 2016
The treatment of epidermal growth factor receptor (EGFR)-driven non-small cell lung cancers with the T790M resistance mutation remains a significant unmet medical need. We report the identification of 4-aminoindazolyl-dihydrofuro[3,4-d]pyrimidines as non-covalent inhibitors of EGFR, with excellent activity against the T790M resistance double mutants and initial single activating mutants. Using an optimization strategy focused on structure-based design and improving PK properties through metabolite identification, we obtained advanced leads with high oral exposure.
PubMed | Evotec, Proteros biostructures, Genentech and Pharmaron Beijing Co.
Type: | Journal: Journal of medicinal chemistry | Year: 2016
We report here structure-guided optimization of a novel series of NF-B inducing kinase (NIK) inhibitors. Starting from a modestly potent, low molecular weight lead, activity was improved by designing a type 11/2 binding mode that accessed a back pocket past the methionine-471 gatekeeper. Divergent binding modes in NIK and PI3K were exploited to dampen PI3K inhibition while maintaining NIK inhibition within these series. Potent compounds were discovered that selectively inhibit the nuclear translocation of NF-B2 (p52/REL-B) but not canonical NF-B1 (REL-A/p50).
PubMed | Genentech and Pharmaron Beijing Co.
Type: Journal Article | Journal: ACS medicinal chemistry letters | Year: 2017
Shi Y.-C.,CAS Shanghai Institute of Organic Chemistry |
Yang R.-F.,CAS Shanghai Institute of Organic Chemistry |
Yang R.-F.,Pharmaron Beijing Co. |
Gao D.-W.,CAS Shanghai Institute of Organic Chemistry |
You S.-L.,CAS Shanghai Institute of Organic Chemistry
Beilstein Journal of Organic Chemistry | Year: 2013
When Boc-L-Val-OH was used as a ligand for the enantioselective Pd(II)-catalyzed annulation of N,N-substituted aminomethyl ferrocene derivatives with diarylethynes, ferrocenes with planar chirality could be achieved with excellent enantioselectivity (up to 99% ee). © 2013 Shi et al.
PubMed | Jining Medical University and Pharmaron Beijing Co.
Type: | Journal: Biomedical chromatography : BMC | Year: 2016
Lycopus lucidus Turcz has been used as a traditional phytomedicine for menstrual disorder, amenorrhea, menstrual cramps, inflammation and cardiovascular diseases. However, there is not enough information about identification and quantification for the chemical constituents of L. lucidus Turcz. In this work, a simple, rapid and sensitive UHPLC-Q-TOF-MS method was developed for characterization and identification of the phytochemical compositions in L. lucidus Turcz in negative ion mode. A total of 37 compounds, including 15 phenolic acids, 12 flavonoids, three triterpenoids and seven organic acids were tentatively characterized and identified by means of the retention time, accurate mass and characteristic fragment ions. Thirteen compounds were reported for the first time in L. lucidus Turcz. Among of them, 11 compounds were further quantified by multiple reactions monitoring. The results showed good performance with respect to linearity (r>0.9959), repeatability (RSD<2.6%), intra- and inter-day precision (RSD<3.2%), recovery (93.1-104.9%), and lower limit of quantification (5-50ng/mL). Subsequently, the results were analyzed and classified by hierarchical cluster analysis. The research could be applied for identification and quality evaluation for L. lucidus Turcz.
Bian L.,Pharmaron Beijing. Co. |
Journal of Labelled Compounds and Radiopharmaceuticals | Year: 2015
Ceftazidime is a third generation cephalosporin antibiotic that has activity against a wide range of Gram-negative and Gram-positive bacterial pathogens, including Escherichia coli and Pseudomonas aeruginosa. Stable isotope-labeled ceftazidime was required for use as an internal standard in LC-MS/MS assays, and a route was developed to make [2H6]ceftazidime in eight steps from the commercially available labeled starting material [2H7]isobutyric acid. © 2015 John Wiley & Sons, Ltd.
PubMed | Astrazeneca and Pharmaron Beijing Co.
Type: Journal Article | Journal: Journal of labelled compounds & radiopharmaceuticals | Year: 2016
As part of a Medicinal Chemistry program aimed at developing an orally bioavailable selective estrogen receptor degrader, a number of tritium, carbon-14, and stable isotope labelled (E)-3-[4-(2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl]prop-2-enoic acids were required. This paper discusses 5 synthetic approaches to this compound class.