SB273005

SB 273005 is a potent nonpeptide antagonist of αvβ3 (vitronectin receptor), with Ki values of 1.2 nM and 0.3 nM to two closely related integrins, αvβ3 and αvβ5, respectively [1].

αvβ3 belongs to the integrin family of adhesion molecules. It is a heterodimer. It mediates cell adhesion to serum proteins and extracellular matrix via the recognition of the arg-gly-asp (RGD) sequence [1].

SB 273005 binds αvβ3 and αvβ5 with low nM affinity, but binds weakly to integrins αIIbβ3 and α5β1. SB 273005 inhibits αvβ3-mediated cell adhesion with an IC50 value of 3 nM, endothelial cell migration with an IC50 of 1.8 nM, and osteoclast-mediated bone resorption with an IC50 of 11 nM in vitro [1].

The αvβ3 integrin is pivotal in bone resorption [2]. In the chronic ovx and thyroparathyroidectomized bone resorption rat models, SB 273005 as well as other similar vitronectin receptor antagonists, inhibit bone loss. In AIA rats, prophylactical treatment with SB 273005 at doses of 60, 30, and 10 mg/kg twice daily significantly normalized bone mineral density (BMD). Normalization values of BMD were 69%, 42%, and 44% for doses of 60, 30, and 10 mg/kg twice daily, respectively. A single daily dose of SB 273005 significantly improved BMD (24% normalization) only when SB 273005 was prophylactically administered at 60 mg/kg [1].

References:
[1].  Badger AM, Blake S, Kapadia R, et al. Disease-modifying activity of SB 273005, an orally active, nonpeptide αvβ3 (vitronectin receptor) antagonist, in rat adjuvant-induced arthritis. Arthritis & Rheumatism, 2001, 44(1): 128-137.
[2].  Murphy MG, Cerchio K, Stoch SA, et al. Effect of L-000845704, an αvβ3 integrin antagonist, on markers of bone turnover and bone mineral density in postmenopausal osteoporotic women. The Journal of Clinical Endocrinology & Metabolism, 2005, 90(4): 2022-2028.

Modulation of interactions of neuroblastoma cell lines with extracellular matrix proteins affects their sensitivity to treatment with the anti-GD2 ganglioside antibody 14G2a.[Pubmed:28393238]

Int J Oncol. 2017 May;50(5):1899-1914.

Children diagnosed with high risk neuroblastoma have poor prognosis which stimulates efforts to broaden therapies of the neoplasm. GD2-ganglioside (GD2) marks neuroblastoma cells and is a target for monoclonal antibodies. We have recently shown that some neuroblastoma cell lines are sensitive to direct cytotoxicity of the anti-GD2 mouse monoclonal antibody 14G2a (mAb). For IMR-32 and LA-N-1 cell lines, treatment with the 14G2a mAb induced evident changes in appearance such as cell rounding, aggregation, loose contact with culture plastic, or detachment. Such findings prompted us to investigate whether modulation of attachment of neuroblastoma cells to extracellular matrix (ECM) proteins can affect their sensitivity to the 14G2a mAb treatment. First, using ultra-low attachment plates, we show that survival of the IMR-32, LA-N-1, LA-N-5, CHP-134 and Kelly cells depends on attachment. Next, we compared cellular ATP levels of the cell lines treated with the 14G2a mAb using uncoated, fibronectin-, collagen IV-coated surfaces to show that the ECM proteins slightly modulate sensitivity of the cell lines to the mAb. Then, we characterized presence of selected integrin subunits or their complexes on the cell surface. Finally, we applied small molecule inhibitors of selected integrin complexes: obtustatin (inhibiting alpha1beta1 heterodimer), BIO 1211 (inhibiting active alpha4beta1 heterodimer), cilengitide and SB273005 (inhibitors of alphaVbeta3, alphaVbeta5 heterodimers) to verify their effects on attachment of cell lines, cellular ATP levels, and in some experiments activities of apoptosis-executing caspase-3 and -7, for the compounds used alone or in combination with the 14G2a mAb. We characterized levels of total FAK (focal adhesion kinase), p-FAK (Tyr397) in IMR-32 cells treated with BIO 1211, and in LA-N-5, Kelly and SK-N-SH cells treated with SB273005. Our results extend knowledge on factors influencing cytotoxicity of 14G2a.