Exploring the structural requirements for inhibition of the ubiquitin E3 ligase breast cancer associated protein 2 (BCA2) as a treatment for breast cancer.
The zinc-ejecting aldehyde dehydrogenase (ALDH) inhibitory drug disulfiram (DSF) was found to be a breast cancer-associated protein 2 (BCA2) inhibitor with potent antitumor activity. We herein describe our work in the synthesis and evaluation of new series of zinc-affinic molecules to explore the structural requirements for selective BCA2-inhibitory antitumor activity. An N(C=S)S-S motif was found to be required, based on selective activity in BCA2-expressing breast cancer cell lines and against recombinant BCA2 protein. Notably, the DSF analogs (3a and 3c) and dithio(peroxo)thioate compounds (5d and 5f) were found to have potent activity (submicromolar IC(50)) in BCA2 positive MCF-7 and T47D cells but were inactive (IC(50) > 10 microM) in BCA2 negative MDA-MB-231 breast cancer cells and the normal breast epithelial cell line MCF10A. Testing in the isogenic BCA2 +ve MDA-MB-231/ER cell line restored antitumor activity for compounds that were inactive in the BCA2 -ve MDA-MB-231 cell line. In contrast, structurally related dithiocarbamates and benzisothiazolones (lacking the disulfide bond) were all inactive. Compounds 5d and 5f were additionally found to lack ALDH-inhibitory activity, suggestive of selective E3 ligase-inhibitory activity and worthy of further development.
Brahemi
Ghali
G
Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff, CF10 3NB, Wales, United Kingdom.
Kona
Fathima R
FR
Fiasella
Annalisa
A
Buac
Daniela
D
Soukupová
Jitka
J
Brancale
Andrea
A
Burger
Angelika M
AM
Westwell
Andrew D
AD
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D045744:Cell Line, Tumor; D004221:Disulfiram / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D004795:Enzyme Stability; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects; D015032:Zinc / Q000378:metabolism
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000444:Aldehyde Dehydrogenase; C506934:RNF115 protein, human; D044767:Ubiquitin-Protein Ligases; D015032:Zinc; D004221:Disulfiram