Development of PFKFB3 blockers for anti-angiogenic tumor therapy

Tumors abuse blood vessels to obtain oxygen and nutrients and to metastasize. The success of blocking the growth of new blood vessels (angiogenesis) to starve tumors and prevent metastasis by inhibiting pro-angiogenic factors is limited by insufficient efficacy and the development of resistance. Hence, there is a large unmet medical need for more efficient anti-angiogenic therapies, based on entirely different concepts. We found that endothelial cells (ECs, lining blood vessels) are highly glycolytic. Actively sprouting ECs like tumor ECs further upregulate glycolysis, and partial and transient inhibition of this excess glycolysis by genetic or pharmacological inhibition of the glycolytic enzyme phosphofructokinase-2/fructose-2,6-bisphosphatase-3 (PFKFB3), inhibits pathological angiogenesis. Moreover, partial inhibition of PFKFB3 in preclinical mouse tumor models induces normalization of the otherwise abnormalized tumor vessels. Orally available small molecule compounds to specifically inhibit PFKFB3's kinase activity are not clinically available. Therefore, developing a novel specific and potent PFKFB3 blocking compound with a superior pharmacological profile would represent a major progress. Here, we (VIB-KU Leuven CCB, Belgium and CNCL/NCDS, China) will bring together our longstanding expertises in EC metabolism and high-throughput compound screening to identify first-in-class PFKFB3 inhibitors. We ultimately aim at seeing such compounds entering clinical trials.