Objective

The major ambition in cancer drug discovery is to selectively kill malignant cells minimizing toxic effects in normal cells. The heterogeneity and plasticity of the tumour microenvironment (TME) provide a real challenge to cancer therapy primarily because of treatment resistance and disease recurrence. A common feature of most solid tumours is hypoxia (low oxygen tension) which arises from a mismatch between oxygen supply and oxygen demand within the tumour due to a combination of impaired vasculature and increased cell proliferation. Intratumoral hypoxia initiates an adaptive response highly mediated by the hypoxia inducible factors (HIFs), the master transcriptional regulators of genes promoting glycolysis, angiogenesis, increased genetic instability and cell survival. Clinically, hypoxia is associated with tumour progression, metastasis, resistance to conventional therapies and poor patient prognosis. Therefore, exploiting hypoxia signalling responses in cancer is currently an attractive approach for therapeutic intervention. Some years ago our lab developed a robust hypoxia cell-based screen (1) designed on HIF pathway activation, to identify small molecule inhibitors of HIF/hypoxia responses. Through setting up a rigorous test cascade, we have progressed with a potent lead hit series of compounds with desirable drug-like properties that cover a novel chemical space. We are currently at the stage of de-convoluting the mechanism of action and identifying the target(s) of our nominated lead series using genetic and proteomic approaches, with the goal of progressing towards lead optimization and clinical application.

References: 1. Chau NM et al., Cancer Res. 2005, 65(11):4918-28.