Integrins a family of heterodimeric adhesion receptors for diverse extracellular matrices, have consistently been implicated as crucial drivers of ovarian cancer development and progression. A number of the RGD-based members of the integrin family, including α5β1, and αvβ3 or αvβ5 integrins, are markedly elevated in aggressive ovarian tumors. These adhesion receptors appear to promote cell adhesion, survival, motility and invasion during ovarian tumor growth or metastatic progression. Importantly, the functions of these integrins are strongly dependent on the activation of focal adhesion kinase (FAK) and its downstream signaling, including the PI3K/Akt- and Ras/MAPK-dependent pathways.
Integrins are transmembrane proteins and are major receptors for cell-extracellular matrix (ECM) and cell-cell adhesion. Modulation of these molecules, particularly αv integrin family, has exhibited profound effects on fibrosis in multiple organ and disease state. Based on the several studies, the integrins αvβ3, αvβ5, αvβ6, and αvβ8 have been known to modulate the fibrotic process via activation of latent transforming growth factor (TGF)-β in pre-clinical models of fibrosis.
Each integrin is typically formed by the non-covalent pairing of one α subunit, of which, 18 types are known to exist, and one β subunit, of which 8 types are known to exist. Together, 24 distinct heterodimers have been identified to date. The αv subunit can form heterodimers with the β1, β3, β5, β6 or β8 subunits and β1 can associate with many different α subunits from α1 to α11, and αv, indicating that not all theoretically possible α and subunit pairs form. Interestingly, the activation of TGF-β appears to be a common function of multiple αv integrins.
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Cyclo(RGDyK) (Cyclic Arg-Gly-Asp-D-Tyr-Lys) is a cyclic derivative of RGD, potent, selective αVβ3 integrin inhibitor with IC50 of 20 nM; a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins including αvβ3.
A RGD pipetide, potent and selective αvβ3 integrin inhibitor with Kd of 41.7 nM; shows strong inhibitory effect on the proliferation of T-24 cells; induces less tumor progression, less tumor metabolic activity, fewer intratumoral vessels in mice model.
A novel active RGD peptidomimetic inhibitor of αv integrin with IC50s of 1.8/0.8/61/1.5/0.2 nM for αvβ1/αvβ3/αvβ5/αvβ6/αvβ8; no inhibition on αIIbβ3, α2β1 and α10β1 (>50 uM); significantly inhibits progression of pulmonary fibrosis in mice model.
SC-68448 (SC68448) is a potent, selective peptidomimetic antagonist of the integrin αvβ3 with IC50 of 1 nM, 100-fold selectivity over αIIbβ3; inhibits alpha(v)beta3-mediated endothelial cell proliferation in a dose-dependent manner but did not inhibit tumor cell proliferation in cell-based assays; inhibits angiogenesis in vivo in a basic fibroblast growth factor-induced rat corneal neovascularization model.
Valategrast is a potent, α4β1 (VLA-4) and α4β7 dual antagonist.
Valategrast hydrochloride is a potent, α4β1 (VLA-4) and α4β7 dual antagonist.
AJM300 (AJM 300, AJM-300) is a novel potent, selective, oraaly available alpha 4 integrin antagonist fortreatment of active ulcerative colitis.
A novel potent, orally active ILK (integrin-linked kinase) inhibitor with IC50 of 0.6 uM; exhibits high in vitro potency against a panel of prostate and breast cancer cell lines (IC50=1-2.5 uM) with no effect on normal epithelial cells; facilitates the dephosphorylation of Akt at Ser-473 and other ILK targets, including GSK-3β and myosin light chain; suppresses the expression of the transcription/translation factor YB-1 and HER2, EGFR in PC-3 cells, induces autophagy and apoptosis; demonstrates in vivo efficacy in suppressing PC-3 xenograft tumor growth; orally active.
GLPG-0187 (GLPG0187) is a highly potent, broad spectrum integrin receptor antagonist with IC50 of 1-10 nM for αvβ1, αvβ3, αvβ5, αvβ6, αvβ8 and α5β1; significantly inhibits angiogenesis both in vivo and in vitro, osteoclastogenesis in vitro, and bone loss in vivo; inhibits de novo formation and progression of bone and visceral metastases in prostate cancer and breast cancer mice models.
A potent LFA-1/ICAM-1 antagonist with IC50 of 9 nM in HuT78 cells; exhibits good in vitro safety profile and low potency on CYP3A4, CYP2C9 and hERG; development as an ophthalmic solution for treating dry eye.
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