- Potent antiproliferative activity of bradykinin B2 receptor selective agonist FR-190997 and analogue structures thereof: A paradox resolved?
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Βradykinin stimulation of B2 receptor is known to activate the oncogenic ERK pathway and overexpression of bradykinin receptors B1 and B2 has been reported to occur in glioma, colorectal and cervical cancers. B1R and B2R antagonists have been shown to reverse tumor proliferation and invasion. Paradoxically, B1R and B2R agonism has also been reported to elicit antiproliferative benefits. In order to complement the data accumulated to date with the natural substrate bradykinin and peptidic B2R antagonists, we decided to examine for the first time the response elicited by B2R stimulation in breast cancer lines with a non-peptidic small molecule B2R agonist. We synthesized and assessed the highly selective and potent B2R partial agonist FR-190997 in MCF-7 and MDA-MBA-231 breast cancer lines and found it possessed significant antiproliferative activity (IC50 2.14 and 0.08 μΜ, respectively). The modular nature of FR-190997 allowed us to conduct a focused SAR study and discover compound 10 which exhibits subnanomolar antiproliferative activity (IC 50 0.06 nΜ) in the TNBC MDA-MBA-231 cell line. This performance surpasses, in most cases by several orders of magnitude, those of established anticancer agents and FDA-approved breast cancer drugs. In line with the established literature we suggest that this remarkable activity precipitates from a dual mode of action involving agonist-induced receptor internalization/degradation combined with sequestration of functional intracellular B2 receptors and inhibition of the associated endosomal signaling. The latter mode may be realized by appropriate ligands regardless of B2R agonist/antagonist designation which only relates to membrane residing GCPRs. Under this prism the controversy over the antiproliferative effects of B2 agonists and antagonists is potentially neutralized.
- Rassias, Gerasimos,Leonardi, Sofia,Rigopoulou, Dionisia,Vachlioti, Eleanna,Afratis, Konstantinos,Piperigkou, Zoi,Koutsakis, Christos,Karamanos, Nikos K.,Gavras, Haralambos,Papaioannou, Dionissios
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supporting information
(2020/11/12)
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- Heterocyclic compounds
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The inventive subject matter relates to compounds, pharmaceutical compositions, and kits containing a heterocyclic compound represented by the formula (I) wherein R is an alkyl group optionally having substituent(s) etc., X is an amino group optionally having substituent(s), Y1 and Y2 are nitrogen atoms etc., an isomer or solvate thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
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Page/Page column 13
(2010/02/14)
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- A novel class of orally active non-peptide bradykinin B2 receptor antagonists. 1. Construction of the basic framework
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A novel class of potent, selective, and orally active non-peptide bradykinin (BK) B2 receptor antagonists were designed and synthesized starting from 8-benzyloxyimidazo[1,2-α]pyridine derivative 2. The unique screening lead (2) was discovered b
- Abe, Yoshito,Kayakiri, Hiroshi,Satoh, Shigeki,Inoue, Takayuki,Sawada, Yuki,Imai, Keisuke,Inamura, Noriaki,Asano, Masayuki,Hatori, Chie,Katayama, Akira,Oku, Teruo,Tanaka, Hirokazu
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p. 564 - 578
(2007/10/03)
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- IMIDAZO [1,2-A] PYRIDINES AND THEIR PHARMACEUTICAL USE
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The invention relates to novel bradykinin antagonists of the formula: STR1 wherein R 1 is halogen,R 2 and R 3 are each hydrogen, lower alkyl, halo(lower)alkyl or acyl,R 4 is aryl having suitable substituent(s), or a heterocyclic group optionally having suitable substituent(s),Q is O or N--R 11, in which R 11 is hydrogen or acyl, andA is lower alkylene,and pharmaceutically acceptable salts thereof.
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