The Discovery of VX-745: A Novel and Selective p38α Kinase Inhibitor

Duffy, John P.; Harrington, Edmund; Salituro, Francesco G.; Cochran, John E.; Green, Jeremy; Gao, Huai; Bemis, Guy W.; Evindar, Ghotas; Galullo, Vincent; Ford, Pamella J.; Germann, Ursula A.; Wilson, Keith; Bellon, Steven F.; Chen, Guanging; Taslimi, Paul; Jones, Peter L.; Huang, Cassey; Pazhanisamy, S.; Wang, Yow‐Ming; Murcko, Mark A.; Su, Michael

doi:10.1021/ml2001455

Cited by 72 publications

(65 citation statements)

References 27 publications

(39 reference statements)

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“…Unfortunately,B IRB-796, [19,20] Scio-469, [19,21] BMS-582949, [19,22] We identified al ead series of p38 mitogen-activatedp rotein kinase inhibitors using as tructure-based design strategy from high-throughput screeningo fh it compound 1.X -ray crystallographyo f1 with the kinase showed an infrequent flip of the peptideb ond between Met109a nd Gly110, which was considered to lead to high kinase selectivity.O ur structure-based design strategy was to conducts caffold transformation of 1 with maintenanceo fh ydrogen bond interactions with the flipped hinge backboneo ft he enzyme. Kaieda VX-702, [19,23,24] ,R o-4402257, [19,25] and TAK-715 [16,26] have been discontinued, mainly owing to lack of efficacy.H owever,o ther inhibitors, including VX-745, [19,27] BCT-197, LY-2228820, GW856553, [19,28,29] PH-797804,A ZD-7624, CHF-6297, FX-005, and ARRY-797, [19] have been examined in phase II clinical trials ( Figure 2). Of the compounds evaluated, 21 was found to be ap otent inhibitor of the p38 MAP kinase, lipopolysaccharide-induced tumor necrosis factor-a (TNF-a)p roduction in human monocytic leukemia cells, and TNF-a-induced production of interleukin-8inhuman whole bloodcells.…”

Section: Introductionmentioning

confidence: 99%

Structure‐Based Design, Synthesis, and Biological Evaluation of Imidazo[4,5‐b]pyridin‐2‐one‐Based p38 MAP Kinase Inhibitors: Part 1

et al. 2019

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We identified a lead series of p38 mitogen‐activated protein kinase inhibitors using a structure‐based design strategy from high‐throughput screening of hit compound 1. X‐ray crystallography of 1 with the kinase showed an infrequent flip of the peptide bond between Met109 and Gly110, which was considered to lead to high kinase selectivity. Our structure‐based design strategy was to conduct scaffold transformation of 1 with maintenance of hydrogen bond interactions with the flipped hinge backbone of the enzyme. In accordance with this strategy, we focused on scaffold transformation to identify imidazo[4,5‐b]pyridin‐2‐one derivatives as potent inhibitors of the p38 MAP kinase. Of the compounds evaluated, 21 was found to be a potent inhibitor of the p38 MAP kinase, lipopolysaccharide‐induced tumor necrosis factor‐α (TNF‐α) production in human monocytic leukemia cells, and TNF‐α‐induced production of interleukin‐8 in human whole blood cells. Herein we describe the discovery of potent and orally bioavailable imidazo[4,5‐b]pyridin‐2‐one‐based p38 MAP kinase inhibitors that suppressed cytokine production in a human whole blood cell‐based assay.

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Section: Introductionmentioning

confidence: 99%

Structure‐Based Design, Synthesis, and Biological Evaluation of Imidazo[4,5‐b]pyridin‐2‐one‐Based p38 MAP Kinase Inhibitors: Part 1

et al. 2019

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“…Neflamapimod (previously code‐named VX‐745)18 is a highly selective oral small molecule inhibitor of p38 α that after oral administration in animals achieves brain concentrations that are ~twofold higher than in blood 16, 19, 20. Following phase 1 studies in healthy volunteers and a phase 2a study in patients with rheumatoid arthritis, neflamapimod was repositioned as a CNS therapeutic 16.…”

Section: Introductionmentioning

confidence: 99%

An exploratory clinical study of p38α kinase inhibition in Alzheimer's disease

Scheltens

Prins

Lammertsma

et al. 2018

Ann Clin Transl Neurol

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ObjectiveThe aim of this study was to preliminarily evaluate an oral small molecule p38α kinase inhibitor in patients with early Alzheimer's disease (AD) for the effects on brain amyloid plaque load and episodic memory function, and to establish pharmacokinetic–pharmacodynamics correlations if any effects identified on these parameters.MethodsSixteen patients with early AD received a highly selective p38α inhibitor (neflamapimod) for 84 days (12 weeks). To obtain a broad range of plasma drug exposures, subjects randomized to receive either 40 mg (n = 9) or 125 mg (n = 7) twice daily. Dynamic, 11C‐PiB positron emission scans were performed at baseline and at Day 84 and quantitatively analyzed by reference parametric mapping. Episodic memory assessed as Wechsler Memory Scale (WMS) immediate and delayed recall composites.ResultIn the 11C‐PiB analyses there were no main group level effects, though in the prespecified responder analysis (>7% reduction in 11C‐PiB signal) there were three responders in the 40 mg, and one in the 125 mg group. There were statistically significant increases from baseline in mean WMS immediate recall score and WMS delayed recall at both day 28 (P = 0.03 and P = 0.001) and day 84 (P = 0.001 and P < 0.001). Individual subject plasma drug concentration profiles were significantly positively correlated with the change in combined WMS immediate and delayed recall (P < 0.0001, r 2= 0.70). Within‐subject effect size was 0.59 for immediate recall and 0.67 for delayed recall.InterpretationSelective p38α inhibition in patients with early AD may improve episodic memory and potentially impact β‐amyloid production. These preliminary clinical findings support conduct of a longer duration placebo‐controlled study, particularly to confirm the effects on episodic memory function.

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“…GW-2580 [31] is ranked first by S(pKd5), WS(pKd1) and WS(pKd0.5), though the global ranking of the compounds over each metric is quite different. VX-745 [38] is ranked first by S(pKd6), WS(pKd1) and WS(pKd0.5).…”

Section: Resultsmentioning

confidence: 99%

The use of novel selectivity metrics in kinase research

2017

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BackgroundCompound selectivity is an important issue when developing a new drug. In many instances, a lack of selectivity can translate to increased toxicity. Protein kinases are particularly concerned with this issue because they share high sequence and structural similarity. However, selectivity may be assessed early on using data generated from protein kinase profiling panels.ResultsTo guide lead optimization in drug discovery projects, we propose herein two new selectivity metrics, namely window score (WS) and ranking score (RS). These metrics can be applied to standard in vitro data–including intrinsic enzyme activity/affinity (Ki, IC50 or percentage of inhibition), cell-based potency (percentage of effect, EC50) or even kinetics data (Kd, Kon and Koff). They are both easy to compute and offer different viewpoints from which to consider compound selectivity.ConclusionsWe performed a comparative analysis of their respective performance on several data sets against already published selectivity metrics and analyzed how they might influence compound selection. Our results showed that the two new metrics bring additional information to prioritize compound selection.Graphical AbstractTwo novel metrics were developed to better estimate selectivity of compounds screened on multiple proteins. Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-016-1413-y) contains supplementary material, which is available to authorized users.

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The Discovery of VX-745: A Novel and Selective p38α Kinase Inhibitor

Cited by 72 publications

References 27 publications

Structure‐Based Design, Synthesis, and Biological Evaluation of Imidazo[4,5‐b]pyridin‐2‐one‐Based p38 MAP Kinase Inhibitors: Part 1

Structure‐Based Design, Synthesis, and Biological Evaluation of Imidazo[4,5‐b]pyridin‐2‐one‐Based p38 MAP Kinase Inhibitors: Part 1

An exploratory clinical study of p38α kinase inhibition in Alzheimer's disease

The use of novel selectivity metrics in kinase research

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