Discovery of structure-based small molecular inhibitor of αB-crystallin against basal-like/triple-negative breast cancer development in vitro and in vivo.
αB-crystallin (CRYAB) is present at a high frequency in poor prognosis basal-like breast tumours, which are largely absent of oestrogen, progesterone receptors and HER2 known as triple-negative breast cancer (TNBC). CRYAB functions as a molecular chaperone to bind to and correct intracellular misfolded/unfolded proteins such as vascular endothelial growth factor (VEGF), preventing non-specific protein aggregations under the influence of the tumour microenvironment stress and/or anti-cancer treatments including bevacizumab therapy. Directly targeting CRYAB can sensitize tumour cells to chemotherapeutic agents and decrease tumour aggressiveness. However, growing evidence shows that CRYAB is a critical adaptive response element after ischemic heart disease and stroke, implying that directly targeting CRYAB might cause serious unwanted side effects. Here, we used structure-based molecular docking of CRYAB and identified a potent small molecular inhibitor, NCI-41356, which can strongly block the interaction between CRYAB and VEGF165 without affecting CRYAB levels. The disruption of the interaction between CRYAB and VEGF165 elicits in vitro anti-tumour cell proliferation and invasive effects through the down-regulation of VEGF signalling in the breast cancer cells. The observed in vitro anti-tumour angiogenesis of endothelial cells might be attributed to the down-regulation of paracrine VEGF signalling in the breast cancer cells after treatment with NCI-41356. Intraperitoneal injection of NCI-41356 greatly inhibits the tumour growth and vasculature development in in vivo human breast cancer xenograft models. Our findings provide 'proof-of-concept' for the development of highly specific structure-based alternative targeted therapy for the prevention and/or treatment of TNBC.
Department of Anatomy and Cell Biology, University of Florida, 1600 SW Archer Road, Gainesville, FL, USA.
Zhijuan
Z
Chen
Qing
Q
Ruan
Song
S
Han
Lei
L
Xi
Wenguo
W
Jiang
Huabei
H
Jiang
David A
DA
Ostrov
Jun
J
Cai
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D055808:Drug Discovery; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D018698:Glutamic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D009389:Neovascularization, Pathologic / Q000378:metabolism; D020836:Protein Structure, Quaternary; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D038203:alpha-Crystallin B Chain / Q000037:antagonists & inhibitors* / Q000737:chemistry
C425779:3-methylglutamic acid; D000970:Antineoplastic Agents; C059215:CRYAB protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D038203:alpha-Crystallin B Chain; D018698:Glutamic Acid