TY - JOUR
T1 - Overcoming Chemical, Biological, and Computational Challenges in the Development of Inhibitors Targeting Protein-Protein Interactions
AU - Laraia, Luca
AU - McKenzie, Grahame
AU - Spring, David R.
AU - Venkitaraman, Ashok R.
AU - Huggins, David J.
N1 - Open access funded by Medical Research Council.
PY - 2015
Y1 - 2015
N2 - Protein-protein interactions (PPIs) underlie the majority of biological processes, signaling, and disease. Approaches to modulate PPIs with small molecules have therefore attracted increasing interest over the past decade. However, there are a number of challenges inherent in developing small-molecule PPI inhibitors that have prevented these approaches from reaching their full potential. From target validation to small-molecule screening and lead optimization, identifying therapeutically relevant PPIs that can be successfully modulated by small molecules is not a simple task. Following the recent review by Arkin et al., which summarized the lessons learnt from prior successes, we focus in this article on the specific challenges of developing PPI inhibitors and detail the recent advances in chemistry, biology, and computation that facilitate overcoming them. We conclude by providing a perspective on the field and outlining four innovations that we see as key enabling steps for successful development of small-molecule inhibitors targeting PPIs.
AB - Protein-protein interactions (PPIs) underlie the majority of biological processes, signaling, and disease. Approaches to modulate PPIs with small molecules have therefore attracted increasing interest over the past decade. However, there are a number of challenges inherent in developing small-molecule PPI inhibitors that have prevented these approaches from reaching their full potential. From target validation to small-molecule screening and lead optimization, identifying therapeutically relevant PPIs that can be successfully modulated by small molecules is not a simple task. Following the recent review by Arkin et al., which summarized the lessons learnt from prior successes, we focus in this article on the specific challenges of developing PPI inhibitors and detail the recent advances in chemistry, biology, and computation that facilitate overcoming them. We conclude by providing a perspective on the field and outlining four innovations that we see as key enabling steps for successful development of small-molecule inhibitors targeting PPIs.
U2 - 10.1016/j.chembiol.2015.04.019
DO - 10.1016/j.chembiol.2015.04.019
M3 - Journal article
SN - 2451-9456
VL - 22
SP - 689
EP - 703
JO - Cell Chemical Biology
JF - Cell Chemical Biology
IS - 6
ER -