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Start Over Author "Magnuson SR" Topic protein kinase inhibitors
3 results on '"Magnuson SR"'

1. Fragment-based identification and optimization of a class of potent pyrrolo[2,1-f][1,2,4]triazine MAP4K4 inhibitors.

Author

Wang L, Stanley M, Boggs JW, Crawford TD, Bravo BJ, Giannetti AM, Harris SF, Magnuson SR, Nonomiya J, Schmidt S, Wu P, Ye W, Gould SE, Murray LJ, Ndubaku CO, and Chen H

Subjects
Animals, Crystallography, X-Ray, Dose-Response Relationship, Drug, Humans, Intracellular Signaling Peptides and Proteins metabolism, Ligands, Mice, Models, Molecular, Molecular Structure, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Protein Serine-Threonine Kinases metabolism, Structure-Activity Relationship, Triazines chemical synthesis, Triazines chemistry, NF-kappaB-Inducing Kinase, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases antagonists & inhibitors, Triazines pharmacology
Abstract

MAP4K4 has been shown to regulate key cellular processes that are tied to disease pathogenesis. In an effort to generate small molecule MAP4K4 inhibitors, a fragment-based screen was carried out and a pyrrolotriazine fragment with excellent ligand efficiency was identified. Further modification of this fragment guided by X-ray crystal structures and molecular modeling led to the discovery of a series of promising compounds with good structural diversity and physicochemical properties. These compounds exhibited single digit nanomolar potency and compounds 35 and 44 achieved good in vivo exposure., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Published
2014
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2. Discovery of selective 4-Amino-pyridopyrimidine inhibitors of MAP4K4 using fragment-based lead identification and optimization.

Author

Crawford TD, Ndubaku CO, Chen H, Boggs JW, Bravo BJ, Delatorre K, Giannetti AM, Gould SE, Harris SF, Magnuson SR, McNamara E, Murray LJ, Nonomiya J, Sambrone A, Schmidt S, Smyczek T, Stanley M, Vitorino P, Wang L, West K, Wu P, and Ye W

Subjects
Animals, Drug Discovery, Female, Intracellular Signaling Peptides and Proteins chemistry, Mice, Models, Molecular, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases chemistry, Pyrimidines pharmacology, Structure-Activity Relationship, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Protein Kinase Inhibitors chemical synthesis, Protein Serine-Threonine Kinases antagonists & inhibitors, Pyrimidines chemical synthesis
Abstract

Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) is a serine/threonine kinase implicated in the regulation of many biological processes. A fragment-based lead discovery approach was used to generate potent and selective MAP4K4 inhibitors. The fragment hit pursued in this article had excellent ligand efficiency (LE), an important attribute for subsequent successful optimization into drug-like lead compounds. The optimization efforts eventually led us to focus on the pyridopyrimidine series, from which 6-(2-fluoropyridin-4-yl)pyrido[3,2-d]pyrimidin-4-amine (29) was identified. This compound had low nanomolar potency, excellent kinase selectivity, and good in vivo exposure, and demonstrated in vivo pharmacodynamic effects in a human tumor xenograft model.

Published
2014
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3. Discovery of potent and selective pyrazolopyrimidine janus kinase 2 inhibitors.

Author

Hanan EJ, van Abbema A, Barrett K, Blair WS, Blaney J, Chang C, Eigenbrot C, Flynn S, Gibbons P, Hurley CA, Kenny JR, Kulagowski J, Lee L, Magnuson SR, Morris C, Murray J, Pastor RM, Rawson T, Siu M, Ultsch M, Zhou A, Sampath D, and Lyssikatos JP

Subjects
Animals, Female, Humans, Janus Kinase 2 metabolism, Mice, Mice, SCID, Models, Molecular, Molecular Structure, Phosphorylation drug effects, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors pharmacokinetics, Pyrimidines chemistry, STAT5 Transcription Factor metabolism, Structure-Activity Relationship, Tissue Distribution, Janus Kinase 2 antagonists & inhibitors, Protein Kinase Inhibitors pharmacology, Pyrimidines pharmacology
Abstract

The discovery of somatic Jak2 mutations in patients with chronic myeloproliferative neoplasms has led to significant interest in discovering selective Jak2 inhibitors for use in treating these disorders. A high-throughput screening effort identified the pyrazolo[1,5-a]pyrimidine scaffold as a potent inhibitor of Jak2. Optimization of lead compounds 7a-b and 8 in this chemical series for activity against Jak2, selectivity against other Jak family kinases, and good in vivo pharmacokinetic properties led to the discovery of 7j. In a SET2 xenograft model that is dependent on Jak2 for growth, 7j demonstrated a time-dependent knock-down of pSTAT5, a downstream target of Jak2.

Published
2012
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