Targeting conventionally intractable cancer-driving proteins: What has been achieved recently?

Abstract

Despite being appealing oncological targets, a majority of cancer-driving proteins with high biomedical relevance remain intractable to conventional small-molecule drug design due to several well-documented challenges. Nonetheless, progress in drug design strategies and experimental techniques has produced far-reaching impact on our efforts in harnessing these undruggable, cancer-driving targets. The past few years have witnessed massive achievements in this field, including the approval of KRASG12C inhibitors, and the successful discovery of investigational new drugs and in vivo potent therapeutics. Herein, we comprehensively depict the strategic landscape for tackling the four classes of undruggable oncoproteins: transcription factors, GTPases, scaffolding proteins, and phosphatases, with a focus on the highly sought-after target(s) within each category. It is anticipated that this overview of strategic strides, along with the perspectives, will guide future innovative drug discovery targeting intractable oncoproteins.