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

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 KRAS^G12C 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.