Benzoxazoles as Transthyretin Amyloid Fibril Inhibitors: Synthesis, Evaluation, and Mechanism of Action

Razavi, Hossein; Palaninathan, S.K.; Powers, Evan T.; Wiseman, R. Luke; Purkey, Hans E.; Mohamedmohaideen, Nilofar N.; Deechongkit, Songpon; Chiang, Kyle P.; Dendle, Maria T. A.; Sacchettini, James C.; Kelly, Jeffery W.

doi:10.1002/anie.200351179

Cited by 214 publications

(188 citation statements)

References 24 publications

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“…In this context, TTR amyloidosis has received widespread attention and several chemical classes of TTR kinetic stabilizers have been reported to date [72]. Among these, a benzoxazole series [73] was further optimized to 2-(3,5-dichlorophenyl)-benzoxazole-6-carboxylic acid (tafamidis; Table 1) [74], a potent TTR stabilizer that has been approved in Europe and Japan for the treatment of transthyretin-related hereditary amyloidosis. Tafamidis binds selectively to TTR variants and stabilizes the TTR dimer interface [74].…”

Section: Tafamidismentioning

confidence: 99%

Stabilization of protein–protein interactions by small molecules

Giordanetto¹,

Schäfer

Ottmann

2014

Drug Discovery Today

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Section: Tafamidismentioning

confidence: 99%

Stabilization of protein–protein interactions by small molecules

Giordanetto¹,

Schäfer

Ottmann

2014

Drug Discovery Today

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“…Cite this article as Cold Spring Harb Perspect Biol 2011;3:a004507 under physiological conditions, precluding amyloidogenesis (Miroy et al 1996;Baures et al 1998Baures et al , 1999Oza et al 1999Oza et al , 2002Klabunde et al 2000;Petrassi et al 2000Petrassi et al , 2005Green et al 2003;Hammarstrom et al 2003;Razavi et al 2003Razavi et al , 2005Adamski-Werner et al 2004;Miller et al 2004;Purkey et al 2004;Green et al 2005;Johnson et al 2005aJohnson et al ,b, 2008aJohnson et al ,b, 2009Wiseman et al 2005;Sekijima et al 2006;Tojo et al 2006;Choi et al 2010a,b;Connelly et al 2010). Tafamidis, a benzoxazole-based transthyretin kinetic stabilizer discovered in academia (Razavi et al 2003) and developed by FoldRx Pharmaceuticals, showing a 2 nM dissociation constant from transthyretin (Razavi et al 2003 Figure 14.…”

Section: Approaches For Adapting Proteostasismentioning

confidence: 99%

“…Another approach is to make the energetics of a specific misfolding-prone proteins less problematic (Miroy et al 1996;Sawkar et al 2002Sawkar et al , 2006aCohen and Kelly 2003;Hammarstrom et al 2003;Razavi et al 2003;Johnson et al 2005bJohnson et al , 2010Tojo et al 2006;Yu et al 2007b;Choi et al 2010a). Because the sequence of a protein specifies its folding, unfolding, misfolding, and aggregation kinetics (the latter being concentration dependent), this would at first glance seem to require sequence reprogramming-the largely unrealized goal of gene therapy.…”

mentioning

confidence: 99%

“…Because the sequence of a protein specifies its folding, unfolding, misfolding, and aggregation kinetics (the latter being concentration dependent), this would at first glance seem to require sequence reprogramming-the largely unrealized goal of gene therapy. However, the energetics of an individual mutant protein prone to misfolding can be selectively tuned, if the folded state of that protein has a hydrophobic depression or cavity to which a small molecule can bind (Miroy et al 1996;Sawkar et al 2002Sawkar et al , 2006aCohen and Kelly 2003;Hammarstrom et al 2003;Razavi et al 2003;Johnson et al 2005b;Tojo et al 2006;Yu et al 2007b;Choi et al 2010a). Small molecules that bind to the native state of mutant proteins lower their folding free energy and thus increase the folded population relative to the unfolded, misfolded, and aggregated states.…”

mentioning

confidence: 99%

“…Indeed, targeting a particular protein prone to misfolding with a small molecule that binds the native state can restore the proteostasis not only of the energetically compromised protein, but of other proteins that use the same proteostasis network components (Gidalevitz et al 2006). Unlike activators of stress-responsive signaling pathways, where one small molecule might be useful for multiple diseases (Mu et al 2008b), native-state-binding small molecules are protein specific (Miroy et al 1996;Fan et al 1999;Fan 2001Fan , 2003Sawkar et al 2002;Hammarstrom et al 2003;Razavi et al 2003;Sekijima et al 2006;Tojo et al 2006).…”

mentioning

confidence: 99%

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Chemical and Biological Approaches for Adapting Proteostasis to Ameliorate Protein Misfolding and Aggregation Diseases-Progress and Prognosis

Lindquist

Kelly²

2011

Cold Spring Harbor Perspectives in Biology

171

139

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Maintaining the proteome to preserve the health of an organism in the face of developmental changes, environmental insults, infectious diseases, and rigors of aging is a formidable task. The challenge is magnified by the inheritance of mutations that render individual proteins subject to misfolding and/or aggregation. Maintenance of the proteome requires the orchestration of protein synthesis, folding, degradation, and trafficking by highly conserved/deeply integrated cellular networks. In humans, no less than 2000 genes are involved. Stress sensors detect the misfolding and aggregation of proteins in specific organelles and respond by activating stress-responsive signaling pathways. These culminate in transcriptional and posttranscriptional programs that up-regulate the homeostatic mechanisms unique to that organelle. Proteostasis is also strongly influenced by the general properties of protein folding that are intrinsic to every proteome. These include the kinetics and thermodynamics of the folding, misfolding, and aggregation of individual proteins. We examine a growing body of evidence establishing that when cellular proteostasis goes awry, it can be reestablished by deliberate chemical and biological interventions. We start with approaches that employ chemicals or biological agents to enhance the general capacity of the proteostasis network. We then introduce chemical approaches to prevent the misfolding or aggregation of specific proteins through direct binding interactions. We finish with evidence that synergy is achieved with the combination of mechanistically distinct approaches to reestablish organismal proteostasis.

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Recent Trends in Structure‐Based Drug Design and Energetics

Andricopulo

Güido

Trivella

et al. 2010

Burger's Medicinal Chemistry and Drug Discovery

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The integration of cheminformatics tools, thermodynamic data, and structural information play a major role in the drug discovery process. Altogether, these methods can describe the molecular forces that govern the affinity and selectivity of bioactive molecules for their macromolecular targets. By being able to uncover the relationships between structure and energetics when using high‐resolution structural information and modern biophysical methods, one can fulfill the challenge of correctly interpreting drug–macromolecular interactions. These interactions are prone to be unveiled and scrutinized when structure‐based drug design is applied to a known three‐dimensional (3D) structure of a given protein. If fully integrated with structure‐based ligand design in an iterative way, computational methods can be of invaluable help to describe the ligand–target (cocomplex) formation. Structure‐based virtual screening can be used to rapid cherry‐pick the best candidates from a large pool of compounds in a chemical library after docking into the active sites of 3D protein structures. To pursue this, the quantification of favorable and unfavorable interactions requires knowledge of the thermodynamics of the interactions. Docking algorithms and molecular dynamics simulations can be used to predict binding energies for positioning ligands in target binding sites, but they only provide information regarded to the prediction of the change in the Gibbs free energy change, which hampers the thoroughly dissection of all other very important thermodynamic parameters—enthalpy, entropy, and heat capacity change. The major goal of this chapter is to show the integration of structure‐based drug design with the energetic. Microcalorimetric measurement of the drug–macromolecular interaction is an effective way to enhance the power, the medicinal chemists have on hand, to pursue a knowledge‐based approach toward the description of all of the noncovalent bond terms that take place in the cocomplex formation.

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Benzoxazoles as Transthyretin Amyloid Fibril Inhibitors: Synthesis, Evaluation, and Mechanism of Action

Cited by 214 publications

References 24 publications

Stabilization of protein–protein interactions by small molecules

Stabilization of protein–protein interactions by small molecules

Chemical and Biological Approaches for Adapting Proteostasis to Ameliorate Protein Misfolding and Aggregation Diseases-Progress and Prognosis

Recent Trends in Structure‐Based Drug Design and Energetics

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