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May 18, 2017

Application of bioinformatics approach to identify indications for PFKFB3-mediated glycolysis inhibition as potential anticancer treatment.

Glycolysis is one of the mechanisms which enables cancer cells to adapt to intermittent oxygen deprivation and obtain the best available metabolic strategy in the lack of resources. Therefore, inhibition of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) enzyme, one of the glycolysis pathway regulators, may result in decreased tumor metabolism, as well as suppressed cell growth. Additionally it has been shown that PFKFB3 is involved in angiogenesis regulation, which contributes to tumor growth, and in immune cells activation, which mediates anti-tumor immune response. Methods: We performed the analysis of available data on the role of PFKFB3 gene expression in various cancer types, i.e. patients’ stratification to identify tumors in which PFKFB3 inhibition improved survival. We exploited TCGA expression data and applied cluster analysis and Cox-regression analysis. The objective was to detect the relation between the increased level of PFKFB3 gene expression and patients’ survival. We also compared the clusters we identified with TCGA metadata to define whether any of them fall down into well-established tumor subtypes. Results: As a result we selected four clusters among solid tumor types, in which increased expression of the target was related to significant decrease in overall survival rate. These include breast cancer, renal cell carcinoma, cervical carcinoma, and leiomyosarcoma. We managed to cross-validate the obtained results on independent datasets. The results show potential indications for PFKFB3 inhibitors. Using our proprietary molecular modelling tool, we designed a series of novel small molecule PFKFB3 inhibitors to target the fructose binding pocket rather than occupying the ATP-pocket which leads to the highly selective inhibition and strong reduction of potential off-target binding. We proved target coverage by performing in vitro biochemical assays. Conclusions: Our current data provide strong rationale for further preclinical and clinical development of PFKFB3 inhibitors as novel anticancer treatment with the potential to overcome resistance to chemo- or radiotherapy.

Published by the American Society of Clinical Oncology (ASCO) - 2017 ASCO Annual Meeting Abstracts
April 24, 2017

DISCOVERY AND CHARACTERIZATION OF A NOVEL PFKFB3 INHIBITOR GO-484 IN A XENOGRAFT MODEL OF TRIPLE-NEGATIVE BREAST CANCER

High level of glycolysis enhances tumor aggressive prolifera on, metastasis, which aggravates disease progression, and mediates drug resistance1. It is associated with increased expression of several genes, including PFKFB3, which encodes a double-func oning enzyme 6-phosphofructo-2-kinase/ fructose-2,6- bisphosphatase-3. It can increase the level of 6-phosphofructo-1-kinase allosteric ac vator - fructose-2,6-bisphosphate, therefore contribu ng to higher glycolysis.

Gero team