scholarly journals β-Lactam Estrogen Receptor Antagonists and a Dual-Targeting Estrogen Receptor/Tubulin Ligand

2014 ◽  
Vol 57 (22) ◽  
pp. 9370-9382 ◽  
Author(s):  
Niamh M. O’Boyle ◽  
Jade K. Pollock ◽  
Miriam Carr ◽  
Andrew J. S. Knox ◽  
Seema M. Nathwani ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Receptor Antagonists ◽  
Dual Targeting ◽  
Estrogen Receptor Antagonists

scholarly journals Towards β-selectivity in functional estrogen receptor antagonists

2012 ◽  
Vol 10 (36) ◽  
pp. 7334 ◽  
Author(s):  
Jose Juan Rodríguez ◽  
Kamila Filipiak ◽  
Maciej Maslyk ◽  
Jakub Ciepielski ◽  
Sebastian Demkowicz ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Receptor Antagonists ◽  
Estrogen Receptor Antagonists

scholarly journals Napyradiomycins A and B1: non-steroidal estrogen-receptor antagonists produced by a Streptomyces.

1993 ◽  
Vol 46 (12) ◽  
pp. 1890-1893 ◽  
Author(s):  
YASUHIRO HORI ◽  
YUKIKO ABE ◽  
NOBUHARU SHIGEMATSU ◽  
TOSHIO GOTO ◽  
MASAKUNI OKUHARA ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Receptor Antagonists ◽  
Steroidal Estrogen ◽  
Estrogen Receptor Antagonists

scholarly journals Estrogen Receptor Antagonists Are Anti-Cryptococcal Agents That Directly Bind EF Hand Proteins and Synergize with Fluconazole In Vivo

mBio ◽  
2014 ◽  
Vol 5 (1) ◽  
Author(s):  
Arielle Butts ◽  
Kristy Koselny ◽  
Yeissa Chabrier-Roselló ◽  
Camile P. Semighini ◽  
Jessica C. S. Brown ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Amphotericin B ◽  
Receptor Antagonists ◽  
Content Type ◽  
New Therapies ◽  
Ef Hand ◽  
Estrogen Receptor Antagonists

ABSTRACT Cryptococcosis is an infectious disease of global significance for which new therapies are needed. Repurposing previously developed drugs for new indications can expedite the translation of new therapies from bench to beside. Here, we characterized the anti-cryptococcal activity and antifungal mechanism of estrogen receptor antagonists related to the breast cancer drugs tamoxifen and toremifene. Tamoxifen and toremifene are fungicidal and synergize with fluconazole and amphotericin B in vitro. In a mouse model of disseminated cryptococcosis, tamoxifen at concentrations achievable in humans combines with fluconazole to decrease brain burden by ~1 log10. In addition, these drugs inhibit the growth of Cryptococcus neoformans within macrophages, a niche not accessible by current antifungal drugs. Toremifene and tamoxifen directly bind to the essential EF hand protein calmodulin, as determined by thermal shift assays with purified C. neoformans calmodulin (Cam1), prevent Cam1 from binding to its well-characterized substrate calcineurin (Cna1), and block Cna1 activation. In whole cells, toremifene and tamoxifen block the calcineurin-dependent nuclear localization of the transcription factor Crz1. A large-scale chemical genetic screen with a library of C. neoformans deletion mutants identified a second EF hand-containing protein, which we have named calmodulin-like protein 1 (CNAG_05655), as a potential target, and further analysis showed that toremifene directly binds Cml1 and modulates its ability to bind and activate Cna1. Importantly, tamoxifen analogs (idoxifene and methylene-idoxifene) with increased calmodulin antagonism display improved anti-cryptococcal activity, indicating that calmodulin inhibition can be used to guide a systematic optimization of the anti-cryptococcal activity of the triphenylethylene scaffold. IMPORTANCE Worldwide, cryptococcosis affects approximately 1 million people annually and kills more HIV/AIDS patients per year than tuberculosis. The gold standard therapy for cryptococcosis is amphotericin B plus 5-flucytosine, but this regimen is not readily available in regions where resources are limited and where the burden of disease is highest. Herein, we show that molecules related to the breast cancer drug tamoxifen are fungicidal for Cryptococcus and display a number of pharmacological properties desirable for an anti-cryptococcal drug, including synergistic fungicidal activity with fluconazole in vitro and in vivo, oral bioavailability, and activity within macrophages. We have also demonstrated that this class of molecules targets calmodulin as part of their mechanism of action and that tamoxifen analogs with increased calmodulin antagonism have improved anti-cryptococcal activity. Taken together, these results indicate that tamoxifen is a pharmacologically attractive scaffold for the development of new anti-cryptococcal drugs and provide a mechanistic basis for its further optimization.

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