LASSBio-542: Novel Thalidomide Analog Distinctly Modulates IL-10 and Inhibits Angiogenesis

Daniel      Serra de Carvalho; Lidia      Moreira Lima; Eliezer      Jesus de Lacerda Barreiro; Tercia      R. Alves; Jose      Augusto da Costa Nery; Euzenir      N. Sarno; Elizabeth      P. Sampaio

Abstract

LASSBio-542 is a thalidomide analog synthesized as a 2-phenoxy-phthalimide derivative with the ability to inhibit Tumor Necrosis Factor-alpha (TNFα), behaving similarly in some instances to the original drug in vitro and in animal models. In new experiments comparing the biological activities of both drugs, we identified LASSBio-542 as an immunomodulator compound with extra properties dissimilar to those of thalidomide. While the extent of TNFα, IL-12p40 and IL-1β production stimulated by Lipopolysaccharide (LPS) inhibition was similar to thalidomide, Interleukin(IL)-10 production was inhibited by LASSBio-542; and Nuclear Factor kappa-B (NFκB) activation via proinflammatory stimulus was also inhibited by both drugs. In the same vein, angiogenesis was impaired while endothelial cell migration was affected by LASSBio-542 alone. Modulation of pro-angiogenic factors induced by TNFα in Human Umbilical Endothelial Vein Cells (HUVEC) such as IL-8, Vascular Endothelial Growth Factor-A (VEGF-A), Cyclooxygenase-2(COX-2), and TNFα itself was also observed by semiquantitative real-time PCR. The study of this molecule may provide new insights into thalidomide mechanisms and new therapeutic options for diseases characterized by singular alterations in the cytokine networks and angiogenesis impairments.

Keywords: Thalidomide, TNFα, IL-10, VEGF, angiogenesis, NFκB, immunomodulator, LASSBio-542, angiogenesis, COX.