Macrocyclic Inhibitors of Hsp90

Johnson, Victoria A.; Singh, Erinprit K.; Nazarova, Lidia A.; Alexander, Leslie D.; McAlpine, Shelli R.

doi:10.2174/156802610792232088

Cited by 40 publications

(24 citation statements)

References 132 publications

(174 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…88 The letter n denotes the number of monomers in the monocyclic polymer. RGD β-lactam peptidomimetics that induce differential gene expression in human endothelial cells, 49 G-quadruplex ligands for anticancer therapeutics, 50 the excellent tumor uptake and pharmacokinetics of 64 Cu-labeled cyclic RGD peptide dimers with Gly and PEG linkers, 51 macrocyclic lactams as potent Hsp90 inhibitors with excellent tumor exposure and extended biomarker activity, 52,53 proteasome inhibitors, 54 inhibitors of HIV-1 capsid-human lysyl-tRNA synthetase, 55 macrocyclic lactams inspired on the skeleton of natural products with anticancer properties, 56 etc. Besides the considered biomedical applications, macrocyclic structures have found important applications in other fields such as chemical analysis 57,58 or nanotechnology.…”

Section: Macrocyclic Compounds Andmentioning

confidence: 99%

Macrocyclization Reactions: The Importance of Conformational, Configurational, and Template-Induced Preorganization

et al. 2015

View full text Add to dashboard Cite

show abstract

Section: Macrocyclic Compounds Andmentioning

confidence: 99%

Macrocyclization Reactions: The Importance of Conformational, Configurational, and Template-Induced Preorganization

et al. 2015

View full text Add to dashboard Cite

show abstract

“…By refolding these proteins, Hsp90 protects them from being degraded, thereby allowing them to promote cell growth or to inhibit apoptotic pathways. 33 …”

mentioning

confidence: 99%

Macrocycles That Inhibit the Binding between Heat Shock Protein 90 and TPR-Containing Proteins

Ardi

Alexander²,

Johnson³

et al. 2011

ACS Chem. Biol.

View full text Add to dashboard Cite

Heat shock protein 90 (Hsp90) accounts for 1–2% of the total proteins in normal cells and functions as a molecular chaperone that folds, assembles, and stabilizes client proteins. Hsp90 is over-expressed (3–6-fold increase) in stressed cells, including cancer cells, and regulates over 200 client and co-chaperone proteins. Hsp90 client proteins are involved in a plethora of cellular signaling events including numerous growth and apoptotic pathways. Since pathway-specific inhibitors can be problematic in drug-resistant cancers, shutting down multiple pathways at once is a promising approach when developing new therapeutics. Hsp90’s ability to modulate many growth and signaling pathways simultaneously makes this protein an attractive target in the field of cancer therapeutics. Herein we present evidence that a small molecule modulates Hsp90 via binding between the N and middle domain and allosterically inhibiting the binding interaction between Hsp90 and four C-terminal binding client proteins: IP6K2, FKBP38, FKBP52, and HOP. These last three clients contain a tetratricopeptide-repeat (TPR) region, which is known to interact with the MEEVD sequence on the C-terminus of Hsp90. Thus, this small molecule modulates the activity between co-chaperones that contain TPR motifs and Hsp90’s MEEVD region. This mechanism of action is unique from that of all Hsp90 inhibitors currently in clinical trials where these molecules have no effect on proteins that bind to the C-terminus of Hsp90. Further, our small molecule induces a Caspase-3 dependent apoptotic event. Thus, we describe the mechanism of a novel scaffold that is a useful tool for studying cell-signaling events that result when blocking the MEEVD-TPR interaction between Hsp90 and co-chaperone proteins.

show abstract

“…[1][2][3][4] The role of macrocycles in medicinal chemistry has been highlighted in many recent reviews. [5][6][7][8][9][10] The efforts are now being focused on functionalization of easily approachable macrocyclic scaffolds with established pharmacophoric groups in search of new drugs for increasingly challenging targets. One such macrocyclic scaffold is calixarene.…”

Section: S P E C I a L I S S U E A R T I C L E Functionalized Calix[4mentioning

confidence: 99%

Functionalized calix[4]arenes as potential therapeutic agents

2017

View full text Add to dashboard Cite

Calixarenes, composed of phenolic units linked by methylene bridges at the 2,6-positions, represent a versatile class of macrocyclic compounds in supramolecular chemistry that can host small molecules or ions in their well-defined hydrophobic cavities. In recent years, it has been recognized that this class of compounds has the potential to serve as platform for the design of biological active compounds. Therefore, the calixarenes functionalized with different pharmacophoric groups have been synthesized as target structure by many researchers and were further evaluated for their biological activities. Owing to their promising biological activities such as antiviral, antibacterial, antifungal, and anticancer, the functionalized calixarenes are recently receiving increased attention from pharmaceutical/medicinal chemistry community. In this review, we summarize and discuss the synthetic approaches and the biological potential of functionalized calixarenes, mainly focusing on the selected recent studies for a comprehensive and target-oriented information, which could help in the design and synthesis of new therapeutic agents leading to the development of clinically viable drugs based on these macrocyles. K E Y W O R D Sbiological activity, calixarenes, cone conformation, functionalization, upper/lower rim/annulus

show abstract

Macrocyclic Inhibitors of Hsp90

Cited by 40 publications

References 132 publications

Macrocyclization Reactions: The Importance of Conformational, Configurational, and Template-Induced Preorganization

Macrocyclization Reactions: The Importance of Conformational, Configurational, and Template-Induced Preorganization

Macrocycles That Inhibit the Binding between Heat Shock Protein 90 and TPR-Containing Proteins

Functionalized calix[4]arenes as potential therapeutic agents

Contact Info

Product

Resources

About