Identification of RIPK1 as a novel target for angiogenesis regulation based on ABT-869 conjugated photoaffinity probes

Angiogenesis plays an important role in the stages of tumor initiation, development, metastasis and invasion. Angiogenesis regulation has gradually emerged as an effective strategy for clinical anti-tumor therapy and prognosis. The discovery and confirmation of new targets for angiogenesis regulation have establish a foundation for the development of novel and original drugs. Receptor-interacting protein kinase 1 (RIPK1), as a key regulator of necroptosis, has recently been found to have a novel function of altering vascular permeability. ABT-869, a multi-target inhibitor against the VEGFR and PDGFR families, has also been shown to be a novel inhibitor of RIPK1-mediated cell necrosis. Therefore, the exploration of whether RIPK1 can be used as the target of vascular permeability regulation and angiogenesis regulation by ABT-869 has high clinical application value. To this end, we adopted a photoaffinity labeling strategy to construct a multifunctional photoaffinity probe based on ABT-869, and verified the feasibility of the strategy with the known target VEGFR-2 as a model. Meanwhile, RIPK1 was identified as a potential angiogenic target of ABT-869 and its activity was further verified. The results of this study are expected to provide a new target for angiogenesis regulation and lay a foundation for the development of novel angiogenesis regulation drugs.