Tissue-specific genes as an underutilized resource in drug discovery

Maria Ryaboshapkina,Mårten Hammar

doi:10.1038/s41598-019-43829-9

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 and PTVesc genes) or direct (elevated betweenness centrality scores 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 show that the opportunities to identify tissue-specific drug targets are not exhausted and discuss potential use cases for tissue-specific genes in drug research.

Highlights

Drug development is a long and costly process
Rouillard and colleagues limited their analysis to drugs with a single mechanism-of-action target and demonstrated that narrow expression profile of a drug target is a robust predictor of success in phase 318
Application of increasingly stringent definitions of tissue-specificity leads to increasingly stronger enrichment of tissue-specific genes among marketed non-oncology drug targets

Summary

Introduction

Drug development is a long and costly process. Selection of the right target is a major factor influencing the probability of success of a drug development program[1,2,3]. Dezso et al observed that tissue-specific genes may represent attractive drug targets due to their role in tissue biology and disease (e.g., brain-specific GABRB2, a receptor for the inhibitory neuromediator gamma-aminobutyric acid, is a target of sedative agents)[12]. Www.nature.com/scientificreports understand the relationship between tissue-specificity and efficacy and apply this knowledge to identify new, and not necessarily only tissue-specific, targets, we may reduce attrition rates in the clinic. With moderately stringent definition (x = 6), we confirm a 2.3-fold enrichment among targets of non-oncology drugs and 1.8-fold enrichment in a pooled analysis for both oncology and non-oncology drug targets, which are similar to the previously published estimates[12,13] We observe that this historic success of tissue-specific targets is not reflected in early clinical trials neither for oncology nor for non-oncology diseases, i.e., tissue-specific targets are underutilized. We find that tissue-specific enzymes and secreted proteins have higher ability to spread perturbations in topological analysis of human protein-protein interactome

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Conclusion