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