A team of researchers from the CMRB directed by Juan Carlos Izpisúa Belmonte has discovered two novel inhibitors of the phosphorylase kinase subunit G1 (PhKG1) that has been identified for the first time to be involved in angiogenesis in vivo. Furthermore, they found that PhKG1 mRNA levels are elevated by more than two-fold in the majority of human tumors (breast, colon, kidney, lung, liver and thyroid), except in prostate cancer. The study was published in Oncogene.
Pathological angiogenesis, the growth of microvessels from existing vasculature, is associated with tumor progression and is a pre-requisite of tumor growth and metastasis. Therefore, inhibitors of angiogenesis are desirable candidates for anti-tumoral therapies.
First, the researchers screened for angiogenesis inhibitors from a compound library of putative kinases from the Dutch company Galapagos, BV, using an automatic quantitative screening assay. They used embryos of a zebrafish line in which the vascular system is visible through endothelial-specific enhanced green fluorescent protein (EGFP) expression. The assay was implemented at the high-throughput screening platform of Biobide SL.
The authors selected two new compounds that were found in the assay as inhibitors of angiogenesis and identified PhKG1 as their target through an in vitro kinase profiling. Finally they confirmed that the two compounds inhibited specifically the angiogenic process of vessel sprouting, as opposed to inhibition of general vasculogenesis, by treating embryos with either drug before the vasculogenic vessels had formed.
Effects of the PhKG1 inhibitors F10 and F11 on the processes of angiogenesis and vasculogenesis
Camus S, Quevedo C, Menéndez S, Paramonov I, Stouten PF, Janssen RA, Rueb S, He S, Snaar-Jagalska BE, Laricchia-Robbio L, Izpisua Belmonte JC. Identification of phosphorylase kinase as a novel therapeutic target through high-throughput screening for anti-angiogenesis compounds in zebrafish. Oncogene. 2011 Dec 19;