Taking Aim at the Undruggable

Abstract

The term “undruggable” is used to describe a protein that is not pharmacologically capable of being targeted; recently, however, substantial efforts have been made to turn these proteins into “druggable” targets. Thus, “difficult to drug” or “yet to be drugged” are perhaps more appropriate terms. In cancer, a number of elusive targets fall into this category, including transcription factors such as STAT3, TP53, and MYC. Pharmacologically targeting these intractable proteins is now a key challenge of modern drug development, requiring innovation and the development of new technologies. In this article, we discuss some of the recent technologic and pharmacologic advances that have underpinned the erosion of the concept of undruggability. We describe recent successes in drugging the undruggable RAS ( KRAS G12C and HRAS), and discuss the advances that have led to the validation of further targets previously believed to be undruggable, such as HIF-2α, BCL-2, MDM2, and MLL. Finally, we look to the future and describe important advances that are likely to have a major impact on targeting undruggable targets, such as the advent of proteolysis-targeting chimeras and protein-protein modulators, which are leading to considerable excitement surrounding the development of cancer targets.

Drug Hunting at the Nexus of Medicinal Chemistry and Chemical Biology and the Discovery of Novel Therapeutic Modalities

“…Proteins that were once thought to be undruggable can now be targeted with small molecules, but the mechanisms of these compounds still generally remain centered on affecting protein function (Figure A) . However, the molecular origins of many diseases are not traced to protein function but rather protein abundance .…”

“…Proteins that were once thought to be undruggable can now be targeted with small molecules, but the mechanisms of these compounds still generally remain centered on affecting protein f unction (Figure 3A). 14 However, the molecular origins of many diseases are not traced to protein function but rather protein abundance. For example, as will be described in more detail below, the devastating pediatric neuromuscular disease spinal muscular atrophy (SMA) is caused by loss of SMN1 and alternative splicing of SMN2, which leads to significantly reduced levels of this essential protein.…”

Selectivity through Targeted Protein Degradation (TPD)

“…The journey that started with the curiosity to understand the underlying mechanism of action of natural products has gone through several high points over the past several decades. A recent milestone on this path is targeted protein degradation. − For a community that has traditionally explored “inhibition” as the popular mechanism of action for undruggable targets, , “degradation” opens up new opportunities for target selection . While the field had soared to new heights in a relatively short period with respect to degrader molecules like PROTACs progressing into the clinic, the selectivity achieved between closely related proteins with some degraders remains more serendipitous.…”

Ex silico engineering of cystine-dense peptides yielding a potent bispecific T cell engager

“…As targeted drug discovery pipelines mature, drug discovery innovation has gradually shifted toward addressing "undruggable" targets with difficult interfaces (1). Alternative strategies beyond simple target inhibition through binding are also maturing, many of which rely on modular design for multiple functions [e.g., chimeric antigen receptors (CARs), bispecific antibodies, and proteolysis-targeting chimeras] (1-3).…”

“…As targeted drug discovery pipelines mature, drug discovery innovation has gradually shifted toward addressing “undruggable” targets with difficult interfaces ( 1 ). Alternative strategies beyond simple target inhibition through binding are also maturing, many of which rely on modular design for multiple functions [e.g., chimeric antigen receptors (CARs), bispecific antibodies, and proteolysis-targeting chimeras] ( 1 – 3 ). Miniproteins are small (roughly <10 kDa in size) proteins that are expanding the toolkit of targeted therapeutics in ways that both small molecules and antibodies are naturally limited ( 4 ).…”