Tissue-specific genes as an underutilized resource in drug discovery

Abstract

Tissue-specific genes are believed to be good drug targets due to improved safety. Here we show that this intuitive notion is not reflected in phase 1 and 2 clinical trials, despite the historic success of tissue-specific targets and their 2.3-fold overrepresentation among targets of marketed non-oncology drugs. We compare properties of tissue-specific genes and drug targets. We show that tissue-specificity of the target may also be related to efficacy of the drug. The relationship may be indirect (enrichment in Mendelian disease genes) or direct (elevated ability to spread perturbations in human protein-protein interactome for tissue-specifically produced enzymes and secreted proteins). Reduced evolutionary conservation of tissue-specific genes may represent a bottleneck for drug projects, prompting development of novel models with smaller evolutionary gap to humans. We highlight numerous open opportunities to use tissue-specific genes in drug research and hope that the current study will facilitate discovery efforts.