Structure-Activity and Structure-Conformation Relationships of Aryl Propionic Acid Inhibitors of the Kelch-like ECH-Associated Protein 1/Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1/NRF2) Protein-Protein Interaction
The KEAP1-NRF2-mediated cytoprotective response plays a key role in cellular homoeostasis. Insufficient NRF2 signaling during chronic oxidative stress may be associated with the pathophysiology of several diseases with an inflammatory component, and pathway activation through direct modulation of the KEAP1-NRF2 protein-protein interaction is being increasingly explored as a potential therapeutic strategy. Nevertheless, the physicochemical nature of the KEAP1-NRF2 interface suggests that achieving high affinity for a cell-penetrant druglike inhibitor might be challenging. We recently reported the discovery of a highly potent tool compound which was used to probe the biology associated with directly disrupting the interaction of NRF2 with the KEAP1 Kelch domain. We now present a detailed account of the medicinal chemistry campaign leading to this molecule, which included exploration and optimization of protein-ligand interactions in three energetic "hot spots" identified by fragment screening. In particular, we also discuss how consideration of ligand conformational stabilization was important to its development and present evidence for preorganization of the lead compound which may contribute to its high affinity and cellular activity.
Heightman, Tom D.,Callahan, James F.,Chiarparin, Elisabetta,Coyle, Joseph E.,Griffiths-Jones, Charlotte,Lakdawala, Ami S.,McMenamin, Rachel,Mortenson, Paul N.,Norton, David,Peakman, Torren M.,Rich, Sharna J.,Richardson, Caroline,Rumsey, William L.,Sanchez, Yolanda,Saxty, Gordon,Willems, Henri?tte M. G.,Wolfe, Lawrence,Woolford, Alison J.-A.,Wu, Zining,Yan, Hongxing,Kerns, Jeffrey K.,Davies, Thomas G.
p. 4683 - 4702
(2019/05/17)
Discovery of selective menaquinone biosynthesis inhibitors against Mycobacterium tuberculosis
Aurachin RE (1) is a strong antibiotic that was recently found to possess 1,4-dihydroxy-2-naphthoate prenyltransferase (MenA) and bacterial electron transport inhibitory activities. Aurachin RE is the only molecule in a series of aurachin natural products that has the chiral center in the alkyl side chain at C9′-position. To identify selective MenA inhibitors against Mycobacterium tuberculosis, a series of chiral molecules were designed based on the structures of previously identified MenA inhibitors and 1. The synthesized molecules were evaluated in in vitro assays, including MenA enzyme and bacterial growth inhibitory assays. We could identify novel MenA inhibitors that showed significant increase in potency of killing nonreplicating M. tuberculosis in the low oxygen recovery assay (LORA) without inhibiting other Gram-positive bacterial growth even at high concentrations. The MenA inhibitors reported here are useful new pharmacophores for the development of selective antimycobacterial agents with strong activity against nonreplicating M. tuberculosis.
Debnath, Joy,Siricilla, Shajila,Wan, Bajoie,Crick, Dean C.,Lenaerts, Anne J.,Franzblau, Scott G.,Kurosu, Michio
p. 3739 - 3755
(2012/07/28)
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