Strategies for targeting undruggable targets

ABSTRACT

Introduction

Undruggable targets refer to clinically meaningful therapeutic targets that are ‘difficult to drug’ or ‘yet to be drugged’ via traditional approaches. Featuring characteristics of lacking defined ligand-binding pockets, non-catalytic protein–protein interaction functional modes and less-investigated 3D structures, these undruggable targets have been targeted with novel therapeutic entities developed with the progress of unconventional drug discovery approaches, such as targeted degradation molecules and display technologies.

Area covered

This review first presents the concept of ‘undruggable’ exemplified by RAS and other targets. Next, detailed strategies are illustrated in two aspects: innovation of therapeutic entities and development of unconventional drug discovery technologies. Finally, case studies covering typical undruggable targets (Bcl-2, p53, and RAS) are depicted to further demonstrate the feasibility of the strategies and entities above.

Expert opinion

Targeting the undruggable expands the scope of therapeutically reachable targets. Consequently, it represents the drug discovery frontier. Biomedical studies are capable of dissecting disease mechanisms, thus broadening the list of undruggable targets. Encouraged by the recent approval of the KRAS inhibitor Sotorasib, we believe that merging multiple discovery approaches and exploiting various novel therapeutic entities would pave the way for dealing with more ‘undruggable’ targets in the future.

KEYWORDS:

• Undruggable target
• Therapeutic entity
• Drug discovery technology
• Protein–protein interaction

Article Highlights

• Unlike traditional druggable targets, undruggable targets exhibit some explicit features: lack of defined ligand-binding pockets, non-catalytic protein–protein interaction function modes, and unclarified 3D structures.

• Innovative therapeutic entities, including bifunctional molecules, covalent drugs, peptide-based drugs, protein-based drugs, and RNA therapeutics, have been developed to conquer undruggable limitations.

• Drug discovery technologies, such as display technologies, DNA-encoded libraries, fragment-based drug discovery, allosteric site hunting, virtual screening, and computer-aided drug design, altogether fuel the screening and rational design of drug candidates.

• Depictions of integrated strategies utilized in the drugging campaigns against three undruggable targets, that is, Bcl-2, p53, and RAS, have guided the future directions.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by grants from the National Natural Science Foundation of China (21907011), the Fundamental Research Funds for the Central Universities (project numbers 2020CQJQY-Z002), and Chongqing Research and Frontier Technology (cstc2020jcyj-jqX0009) awarded to Yizhou Li. This work was also supported by grants from the Fundamental Research Funds for the Central Universities (project No. 2021CDJYGRH—002), awarded to Yangfeng Li, and by grants from the China Postdoctoral Science Foundation (2020M683251), awarded to Gong Zhang.