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Ding H.X.,Pharmacodia Beijing Co. | Leverett C.A.,Pfizer | Kyne R.E.,Pfizer | Liu K.K.-C.,Lilly China Research and Development Center | And 3 more authors.
Bioorganic and Medicinal Chemistry | Year: 2015

New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities (NCEs) provide insight into molecular recognition and also serve as leads for designing future new drugs. This annual review covers the synthesis of twenty-four NCEs that were approved for the first time in 2013 and two 2012 drugs which were not covered during the previous edition of this review. ©2015 Elsevier Ltd. All rights reserved.


Samara E.,PharmaPolaris International Inc. | Shaw J.-P.,Theravance | Shaw J.-P.,Bioduro Inc. | Barriere S.L.,Theravance | And 3 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2012

A population pharmacokinetic model of telavancin, a lipoglycopeptide antibiotic, was developed and used to identify sources of interindividual variability. Data were obtained from healthy subjects (seven phase 1 studies), patients with complicated skin and skin structure infections (cSSSI; two phase 2 and two phase 3 studies), and patients with hospital-acquired pneumonia (HAP; two phase 3 studies). A two-compartment open model with zero-order input best fit the telavancin data from healthy individuals and patients with cSSSI or HAP. Telavancin clearance was highly correlated with renal function and, to a lesser extent, with body weight. Other covariates were related to at least one parameter in cSSSI (gender, bacterial eradication, and surgery) or HAP (age of≥75 years) but did not markedly affect exposure. These analyses support current dosing recommendations for telavancin based on patient weight and renal function. Copyright © 2012, American Society for Microbiology. All Rights Reserved.


Tan J.-A.T.,Beckman Research Institute | Song J.,Beckman Research Institute | Song J.,Bioduro Inc. | Chen Y.,Beckman Research Institute | Durrin L.K.,Beckman Research Institute
Molecular and Cellular Biology | Year: 2010

Special AT-rich sequence-binding protein 1 (SATB1) is a tissue-restricted genome organizer that provides a key link between DNA loop organization, chromatin modification/remodeling, and transcription factor association at matrix attachment regions (MARs). The SUMO E3 ligase PIAS1 enhances SUMO conjugation to SATB1 lysine-744, and this modification regulates caspase-6 mediated cleavage of SATB1 at promyelocytic leukemia nuclear bodies (PML NBs). Since this regulated caspase cleavage occurs on only a subset of SATB1, and the products are relatively stable, proteolysis likely mediates cellular processes other than programmed cell death. However, the mechanism for the spatial and temporal regulation of SATB1 sumoylation and caspase cleavage is not known. Here we report that these processes are controlled by SATB1 phosphorylation; specifically, PIAS1 interaction with SATB1 is inhibited by phosphorylation. Mutagenesis studies identified interaction of the PIAS SAP (scaffold attachment factor-A/B/acinus/PIAS) motif with SATB1 N-terminal sequences. Notably, phosphorylation of SATB1 at threonine-188 regulates its interaction with PIAS1. Sequences near this phosphorylation site, LXXLL (residues 193 to 197), appear to be conserved among a subset of SUMO substrate proteins. Thus, this motif may be commonly involved in interaction with the PIAS SAP, and phosphorylation may similarly inhibit some of these substrates by preventing their interaction with the ligase. Copyright © 2010, American Society for Microbiology. All Rights Reserved.


Jacob L.S.,University of Texas Southwestern Medical Center | Wu X.,University of Texas Southwestern Medical Center | Dodge M.E.,University of Texas Southwestern Medical Center | Fan C.-W.,University of Texas Southwestern Medical Center | And 7 more authors.
Science Signaling | Year: 2011

The Hedgehog (Hh) and Wnt signal transduction pathways are master regulators of embryogenesis and tissue renewal and represent anticancer therapeutic targets. Using genome-wide RNA interference screening in murine cultured cells, we established previously unknown associations between these signaling pathways and genes linked to developmental malformations, diseases of premature tissue degeneration, and cancer. We identified functions in both pathways for the multitasking kinase Stk11 (also known as Lkb1), a tumor suppressor implicated in lung and cervical cancers. We found that Stk11 loss resulted in disassembly of the primary cilium, a cellular organizing center for Hh pathway components, thus dampening Hh signaling. Loss of Stk11 also induced aberrant signaling through the Wnt pathway. Chemicals that targeted the Wnt acyltransferase Porcupine or that restored primary cilia length by inhibiting the tubulin deacetylase HDAC6 (histone deacetylase 6) countered deviant pathway activities driven by Stk11 loss. Our study demonstrates that Stk11 is a critical mediator in both the Hh and the Wnt pathways, and our approach provides a platform to support the development of targeted therapeutic strategies.


Green O.M.,Infection Innovative Medicines Unit | McKenzie A.R.,Infection Innovative Medicines Unit | Shapiro A.B.,Infection Innovative Medicines Unit | Otterbein L.,Valeocon Management Consulting | And 6 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2012

A novel arylsulfonamide-containing series of compounds represented by 1, discovered by highthroughput screening, inhibit the acetyltransferase domain of N-acetylglucosamine-1-phosphate-uridyltransferase/glucosamine-1-phosphate- acetyltransferase (GlmU). X-ray structure determination confirmed that inhibitor binds at the site occupied by acetyl-CoA, indicating that series is competitive with this substrate. This letter documents our early hit-to-lead evaluation of the chemical series and some of the findings that led to improvement in in-vitro potency against Gram-negative and Gram-positive bacterial isozymes, exemplified by compound 40. © 2012 Elsevier Ltd. All rights reserved.

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