Format

Send to

Choose Destination
J Med Chem. 2015 May 14;58(9):3757-66. doi: 10.1021/jm5019252. Epub 2015 May 4.

New inhibitors of angiogenesis with antitumor activity in vivo.

Author information

1
‡CEI Campus Moncloa, UCM-UPM and CSIC, E-28040 Madrid, Spain.
2
∥Instituto de Investigación Hospital 12 de Octubre, E-28041 Madrid, Spain.
3
⊥CIC bioGUNE, Parque Tecnológico de Bizkaia, Edif. 801A, 48160 Derio, Spain.
4
¶Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain.
5
#Departamento de Investigación, Italfarmaco S.A., Calle de San Rafael, 3, E-28108 Alcobendas, Madrid, Spain.

Abstract

Angiogenesis is a requirement for the sustained growth and proliferation of solid tumors, and the development of new compounds that induce a sustained inhibition of the proangiogenic signaling generated by tumor hypoxia still remains as an important unmet need. In this work, we describe a new antiangiogenic compound (22) that inhibits proangiogenic signaling under hypoxic conditions in breast cancer cells. Compound 22 blocks the MAPK pathway, impairs cellular migration under hypoxic conditions, and regulates a set of genes related to angiogenesis. These responses are mediated by HIF-1α, since the effects of compound 22 mostly disappear when its expression is knocked-down. Furthermore, administration of compound 22 in a xenograft model of breast cancer produced tumor growth reductions ranging from 46 to 55% in 38% of the treated animals without causing any toxic side effects. Importantly, in the responding tumors, a significant reduction in the number of blood vessels was observed, further supporting the mechanism of action of the compound. These findings provide a rationale for the development of new antiangiogenic compounds that could eventually lead to new drugs suitable for the treatment of some types of tumors either alone or in combination with other agents.

PMID:
25906180
DOI:
10.1021/jm5019252
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for American Chemical Society
Loading ...
Support Center