Inhibitors of the Lipid Phosphatase SHIP2 Discovered by High Throughput Affinity Selection-Mass Spectrometry Screening of Combinatorial Libraries

Annis, D. Allen; Cheng, Cliff C.; Chuang, Chiashain; McCarter, John D.; Nash, Huw M.; Nazef, Naim; Rowe, Todd; Kurzeja, Robert J.; Shipps, Gerald W.

doi:10.2174/138620709789104870

Cited by 33 publications

(19 citation statements)

References 17 publications

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“…A selective ERK inhibitor was identifi ed using an affi nitybased mass spectroscopy high-throughput platform ( 11 ). A library of approximately 5 million compounds was screened for binding to the unphosphorylated form of the ERK2 protein.…”

Section: Resultsmentioning

confidence: 99%

Discovery of a Novel ERK Inhibitor with Activity in Models of Acquired Resistance to BRAF and MEK Inhibitors

et al. 2013

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The high frequency of activating RAS or BRAF mutations in cancer provides strong rationale for targeting the mitogen-activated protein kinase (MAPK) pathway. Selective BRAF and MAP-ERK kinase (MEK) inhibitors have shown clinical effi cacy in patients with melanoma. However, the majority of responses are transient, and resistance is often associated with pathway reactivation of the extracellular signal-regulated kinase (ERK) signaling pathway. Here, we describe the identifi cation and characterization of SCH772984, a novel and selective inhibitor of ERK1/2 that displays behaviors of both type I and type II kinase inhibitors. SCH772984 has nanomolar cellular potency in tumor cells with mutations in BRAF , NRAS , or KRAS and induces tumor regressions in xenograft models at tolerated doses. Importantly, SCH772984 effectively inhibited MAPK signaling and cell proliferation in BRAF or MEK inhibitor-resistant models as well as in tumor cells resistant to concurrent treatment with BRAF and MEK inhibitors. These data support the clinical development of ERK inhibitors for tumors refractory to MAPK inhibitors. SIGNIFICANCE: BRAF and MEK inhibitors have activity in MAPK-dependent cancers with BRAF or RAS mutations. However, resistance is associated with pathway alterations resulting in phospho-ERK reactivation. Here, we describe a novel ERK1/2 kinase inhibitor that has antitumor activity in MAPK inhibitor-naïve and MAPK inhibitor-resistant cells containing BRAF or RAS mutations. Cancer Discov; 3(7); 742-50.

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Section: Resultsmentioning

confidence: 99%

Discovery of a Novel ERK Inhibitor with Activity in Models of Acquired Resistance to BRAF and MEK Inhibitors

et al. 2013

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“…First, a gradient concentration (10,30,50,75, and 100 mM) and a gradient pH (pH 5.7, 6.2, 6.8, 7.4, and 8.0) of phosphate buffers were used to study the influence of pH and ion strength on the binding experiments. Second, different incubation temperatures (21,30,35,37, and 40°C) and incubation times (10,20,30,40, and 50 min) were evaluated. All the binding assays were performed in duplicate and analyzed as described above.…”

Section: Optimization Conditions For Ligand Screeningmentioning

confidence: 99%

“…It has been widely applied in chemical and pharmaceutical manufacturing, food and beverage processing, and waste water treatment, and so far, particularly in the investigation of the binding degrees of biomacromolecule (i.e., human serum albumin or drug targets) because the binding of the agents to the target macromolecules is the prerequisite for the bioactivities of the agents. High-throughput affinity selection-mass spectrometry screening (i.e., ALIS system) has been successfully applied in screening inhibitors of the lipid phosphatase SHIP2 and ERK from combinatorial libraries [10,11]. Meanwhile, Zhu et al [12] established an ultrafiltration-based approach to screen ligands binding to cyclooxygenase-2 from radix Aconiti extracts and 25 ligands were identified.…”

Section: Introductionmentioning

confidence: 99%

Ultrafiltration coupled with high-performance liquid chromatography and quadrupole-time-of-flight mass spectrometry for screening lipase binders from different extracts of Dendrobium officinale

Tao

Cai

et al. 2015

Anal Bioanal Chem

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Pancreatic lipase plays essential roles in the digestion, transport, and processing of dietary lipids in humans. Inhibition of pancreatic lipase leading to the decrease of lipid absorption may be used for treating obesity. In the present study, a new approach of ultrafiltration coupled with high-performance liquid chromatography and quadrupole-time-of-flight mass spectrometry was established for rapidly detecting lipase binders from different extracts of medicinal plants. Rutin, a model inhibitor of lipase, was selected to optimize the screening conditions, including ion strength, temperature, pH, and incubation time. Meanwhile, the specificity of the approach was investigated by using denatured lipase and inactive compound emodin. The optimal screening conditions were as follows: ion strength 75 mM, temperature 37 °C, pH 7.4, and incubation time 10 min. Furthermore, linearity, accuracy, precision, and matrix effect of the approach were well validated. Finally, lipase binders were screened from different extracts of Dendrobium officinale by applying the established approach and were subsequently subjected to traditional lipase inhibitory assay. Eleven lipase inhibitors were identified, eight of which, namely naringenine, vicenin II, schaftoside, isoschaftoside, isoquercetrin, kaempferol 3-O-β-D-glucopyranoside, vitexin 2″-O-glucoside, and vitexin 2″-O-rhamnoside, were reported for the first time. In addition, docking experiments were performed to determine the preferred binding sites of these new lipase inhibitors.

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“…Within Schering-Plough (now Merck) over the last decade, the "industrially validated" AlIS method has proven to be a robust, reliable, and truly HT methodology [171]. Moreover, it has been supportive in finding new hits and even new leads, with considerable success [171][172][173][174].…”

Section: Target-ligand Screening Assaysmentioning

confidence: 99%

MS Applications in Support of Medicinal Chemistry Sciences

Honing¹,

Ingelse²,

Pramanik³

2013

Mass Spectrometry for Drug Discovery and Drug Development

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In the drug discovery process, medicinal chemistry plays a crucial role in the optimal design and synthesis (production) of new chemical entities (NCEs) or new biological entities (NBEs); this is true for a single entity as well as a complete compound library. A key requirement in this field of science is the optimization of both the chemical and the biological properties of these potential drug-like compounds. Important criteria are the design of efficient synthesis routes, the balancing of the physical chemical properties with optimal in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) processes, and a profound understanding of the pharmacodynamics in the appropriate pharmacological models. In the lead optimization stage, an important step is scaling up the synthesis route as needed for the execution of toxicology studies and the screening of suitable drug formulations. In summary, medicinal chemistry support includes participating in a large variety of activities and decision making processes that play a key role in the search for either a "first in class" new drug or a "best in class" new drug [1].These "drug discovery" processes are continuously under pressure, as the research and development (R&D) costs continue to increase and more data are requested before new drug candidates are taken into (pre-)clinical development. Hence, the choice of "targeted" high-throughput screening (HTS) libraries, the process of hit appraisal, and the understanding of target-ligand interactions can be considered the starting points for a new drug discovery program [2]. Next, the main focus is on the discovery of a lead compound; typically, this is a compound showing promising data regarding target affinity, reasonable efficacy in cellular models, good physical chemical parameters (i.e., a "drug-like" compound), and acceptable oral bioavailability in Mass Spectrometry for Drug Discovery and Drug Development, First Edition. Edited by Walter A. Korfmacher.

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Inhibitors of the Lipid Phosphatase SHIP2 Discovered by High Throughput Affinity Selection-Mass Spectrometry Screening of Combinatorial Libraries

Cited by 33 publications

References 17 publications

Discovery of a Novel ERK Inhibitor with Activity in Models of Acquired Resistance to BRAF and MEK Inhibitors

Discovery of a Novel ERK Inhibitor with Activity in Models of Acquired Resistance to BRAF and MEK Inhibitors

Ultrafiltration coupled with high-performance liquid chromatography and quadrupole-time-of-flight mass spectrometry for screening lipase binders from different extracts of Dendrobium officinale

MS Applications in Support of Medicinal Chemistry Sciences

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