The Cancer Gene Census documents a list of genes which when genetically altered are known to contribute directly to cancer.
A recent paper by Patel et al describes a systematic, computational protocol, that they have used to identify which of these genes code for proteins that would be possible candidate targets, suitable for therapeutic modulation in the treatment of cancer. A suite of analyses were undertaken to explore the biological and chemical space of these proteins (shown below).
Following the computational analysis, the authors prioritize these proteins for drug development. First they identified twenty-five proteins already known to be drug targets, with compounds with full FDA approval. They suggest that some of the compounds may be useful for repurposing in different types of cancer. For instance Smoothened SMO is the target of Vismodegib was recently approved for the treatment of basal cell carcinoma. By mining multi-omic data from The Cancer Genome Atlas the authors suggest that Vismodegib might also be of use in treating Multiforme Glioblastoma (GB), as SMO was over-expressed in 95% of the GB samples analysed.
A further eight-six proteins had active chemical compounds with submicromolar activity in biochemical or binding assays reported in the Chembl database.
They also explored which proteins had a known structure and predicted potential druggable pockets. Figure 2 illustrates the three-dimensional structure of GNAS with the druggable cavity displayed as a surface. GNAS has an activating dominant mutation in pituitary adenoma, and further activating mutations have also been identified in kidney, thyroid, adenocortical, colorectal and Leydig tumours. The authors suggest that small-molecule inhibitors of this enzyme regulator may have potential therapeutic applications.
Of the 488 cancer gene census proteins, the authors identify 103 with good evidence of chemical tractability and group them by “drug development” risk. They identify 46 proteins, whose genes are known to be genetically altered in cancer, whose structures are predicted to be druggable, with few or no know active small molecule modulators, that may be potential therapeutic targets. They suggest that these targets indicate new biological areas for chemical exploration in the treatment of cancer, but they also represent a high potential drug development risk.