Hsp90 Inhibitors
Our Recent publications in the Hsp90 Field
Using NMR to identify binding regions for N and C-terminal Hsp90 inhibitors using Hsp90 domains Jeanette R. McConnell, H. Jane Dyson*, and Shelli R. McAlpine* RSC Med.Chem. V12, p410-415 2021 DOI.: 10.1039/D0MD00387E
C-terminal Hsp90 inhibitors block the HIF-1 hypoxic response by degrading HIF-1a through the oxygen-dependent degradation pathway Nalin Kataria, Chloe-Anne Martinez, Bernadette Kerr, Samantha S. Zaiter, Monica Morgan, Shelli R. McAlpine and Kristina M Cook* Cell. Physiol. Biochem V53, p480-495 2019 DOI: 10.33594/000000152.
Protein-protein inhibitors designed de-novo to target the C-terminus of Hsp90 block co-chaperone activity Marwa N. Rahimi and Shelli R. McAlpine* Chem. Commun. V55, p846-849, 2019 DOI: 10.1039/C8CC07576J
Hsp90 mediates membrane deformation and exosome release Elsa Lauwers,* Yu-Chung Wang, Rodrigo Gallardo, Rob Van der Kant, Emiel Michiels, Jef Swerts, Pieter Baatsen, Samantha S. Zaiter, Shelli R. McAlpine, Natalia V. Gounko, Frederic Rousseau, Joost Schymkowitz, and Patrik Verstreken* Molecular Cell V71, p689-702, e9 2018 DOI: 10.1016/j.molcel.2018.07.016
Synthesis and structure-activity relationships of inhibitors that target the C-terminal MEEVD on Heat shock protein 90 (Hsp90) Marwa N. Rahimi, Laura K. Buckton, Samantha S. Zaiter, Jessica Kho, Vickie Chan, Aldwin Guo, Jenane Konesan, SuHyeon Kwon, Lok K. O. Lam, Michael F. Lawler, Michael Leong, Gabriel D. Moldovan, David A. Neale, Gillian Thornton, and Shelli R. McAlpine* ACS Med. Chem. Lett. V9 p73-77 2018
Redefining the phenotype of Heat shock protein 90 (Hsp90) inhibitors
Yao Wang, Yen Chin Koay, and Shelli R. McAlpine*Chem. Eur. J. V23 2010-2013 2017
How selective are Hsp90 inhibitors for cancer cells over normal cells?
Yao Wang, Yen Chin Koay, and Shelli R. McAlpine*ChemMedChem V12 p353-357 2017
Allosteric Modulators of Heat Shock Protein 90 (HSP90)
Yen Chin Koay and Shelli R. McAlpine * RSC Drug discovery series: “Allosterism in Drug Discovery” DOI:10.1039/9781782629276, p404-426
Three classes of allosteric inhibitors have been described in this chapter. The first were molecules targeting the ATP binding site at the N-terminus of HSP90 (classical inhibitors), while influencing clients that bind to the middle domain. These molecules are the only ones that have reached clinical trials, but they had significant problems including induction of pro-survival responses and dose-limiting toxicities. Thus, these classical inhibitors are being used as part of dual inhibition regiments in current clinical trials. Data was presented in this chapter to suggest that the poor results are also due to the classical inhibitor’s poor selectivity for HSP90 in a cellular environment. Indeed, knocking down HSP90 in cells produces a phenotype that is distinct from that reported with these classical inhibitors. The second class of molecules described are those that bind to the C-terminus (e.g., Novobiocin and KU-174), which have anti-cancer cellular activity without inducing high levels of HSF-1, HSP70, or HSP27. Although these compounds affected several clients that bound to the middle domain, efforts focused on improving the potency and pharmacokinetics of these molecules for in vivo efficacy.
The third class of compounds described are the SM series; these molecules bind between the N- and middle domains of HSP90 but affect the C-terminus. The SM molecules bind to the flexible charged linker region and stop the N-terminus from rotating, thereby blocking access to the C-terminal MEEVD region. By inhibiting access to the MEEVD region, the SM series blocks all co-chaperones with a TRP domain from binding to HSP90. Downstream effects attributed to blocking these co-chaperones produce a reduction of immunophilins FKBP52, and FKBP51, and hormone receptor levels. These SM molecules are also the first to be proven to target HSP90 in the cell. Specifically, as determined using pulldown assays with tagged variants of the molecules in multiple cell lysates, the compounds selectively pull out HSP90. Evaluating their efficacy in cells treated with siRNA for HSP90 we see
that the compounds are more effective when HSP90 is knocked down and less effective when HSP90 is over-expressed. Finally, cells treated with the SM compounds match the phenotype produced when the HSP90 alpha gene is knocked down. Thus, it is possible that there has not yet been a clinical evaluation of HSP90 inhibitors. However, as with all allosteric modulators, there are significant challenges associated with predicting active structures, and as such new direct C-terminal modulators are currently under evaluation.
Reinventing Hsp90 inhibitors: Blocking C-terminal binding events to Hsp90 using dimerized inhibitors
Yen Chin Koay, Hendra Wahyudi, and Shelli R. McAlpine* Chem. Eur. J. V22 p18572-18582 2016
A novel class of Hsp90 C-terminal modulators have preclinical efficacy in prostate tumor cells without induction of a heat shock response
Heather K. Armstrong, Yen Chin Koay, Swati Irani, Rajdeep Das, Zeyad D. Nassar, The Australian Prostate Cancer Bio resource, Luke A. Set, Margaret M. Centenera, Shelli R. McAlpine* and Lisa A. Butler* The Prostate V76, p1546-1559 2016
The first report of direct inhibitors that target the C-terminus MEEVD region on heat shock protein 90
Laura K. Buckton, Hendra Wahyudi, and Shelli R. McAlpine* Chem. Commun. V52, p501-504 2016
Sixteen linear and cyclic peptides were designed de novo and synthesised. Protein binding data indicates that three compounds directly block acccess to heat shock protein 90 (hsp90)’s C-terminus. These molecules are valuable tools useful for investigating the impact of inhibiting hsp90 via a novel mechanism.
Hitting a moving target: How does an N-Methyl group impact biological activity?
Yen Chin Koay, Nicole L. Richardson, Samantha S. Zaiter, Jessica Kho, Sheena Y. Nguyen, Daniel H. Tran, Ka Wai Lee, Laura K. Buckton, and Shelli R. McAlpine* ChemMedChem. V11, p881-892 2016