The evolution of cancer therapeutics: from “undruggable” to “drugged”

Introduction

In recent years, technological progress led to comprehensive molecular profiling in oncology. Based on tumor tissue, liquid biopsies and sophisticated spatio-temporal analysis of tumor-interacting immune-cell-partners (1), our understanding of tumorigenesis was reshaped, enabling precision medicine approaches that stratify patients based on possible actionable alterations (2,3).

Targeted therapies have significantly improved survival across multiple cancer types (3-6). A large meta-analysis of phase II studies linked personalized strategies to superior response rates (31% vs. 10.5%), progression-free survival (PFS; 5.9 vs. 2.7 months), and overall survival (OS; 13.7 vs. 8.9 months) (4), which was validated by two recent meta-analyses (5,6). Benefits extend to poor-prognosis cancers: pancreatic cancer OS increased to 2.58 versus 1.51 years (7), and lung cancer 5-year OS rose from <5% to >25% (PD-L1) and 40% (ALK) (8). Thus, molecular profiling is essential for precise therapy, though many key oncogenic drivers remain “undruggable”.

Here, we discuss key strategies for targeting gene alterations and protein overexpression events previously considered “undruggable”, building upon the review by Juan Luiz Coelho-Silva et al., Targeting “undruggable” cancer proteins: pharmacological challenges and emerging strategies (9). We focus on: (I) the biological and structural basis of undruggability; (II) recent technological advances targeting previously inaccessible proteins; (III) associated major barriers and limitations; (IV) clinically important undruggable targets to shape future cancer therapy; (V) ongoing methodological developments; and (VI) future perspectives for precision oncology.

Reasons for undruggable targets

Limited access to therapies for altered genes or proteins is due to several factors, detailed in (10,11).

• Absence of well-defined ligand-binding pockets that can accommodate small-molecule inhibitors with high affinity;
• Reliance on protein-protein interactions rather than enzymatic activity for biological function;
• Highly conserved active sites among protein family members that preclude selective targeting without off-target effects;
• Intrinsically disordered protein structures that lack stable tertiary conformations amenable to conventional small-molecule inhibition.

For the hallmarks of historically undruggable targets (11), more parameters should be added to reflect their complexity.

• Intracellular localization making them inaccessible to conventional antibodies or drugs;
• Redundant pathway architecture compensating single drug inhibition;
• Epigenetic regulation governed by chromatin state or transcriptional context.

“Undruggability” arises from a combination of structural, functional, and contextual challenges—not a single molecular feature. This complexity helps explain why traditional one-target drug approaches have consistently failed for key oncogenic proteins like MYC, TP53, and RAS (10,12,13).

Recent technological innovations to overcome undruggable targets

The best examples of “undruggable” targets are RAS (the most frequently mutated oncogene, present in approximately 30% of all cancers), TP53 (the most frequently mutated tumor suppressor gene), and MYC (the most frequently amplified oncogene) (12-15). Recent and ongoing technological innovations—including (I) allele-specific covalent inhibitors, (II) proteolysis-targeting chimeras (PROTACs) for targeted protein degradation, (III) molecular glue degraders, and (IV) strategies targeting protein-DNA binding interfaces—have begun to challenge this paradigm and demonstrate clinical proof-of-concept (3,10) (see Figure 1 for a summary of modes of action, timelines, and associated drugs). Yet it must be noted that many of these novel approaches are still in an experimental preclinical or very early clinical stage of development and targeting MYC or TP53 remains challenging and the maturity of clinical data is still limited.

Figure 1 Schematic overview of mechanisms of action, development timelines, and representative drugs for: (I) Allele-specific covalent inhibitors (KRAS G12C) (16-18); (II) proteolysis-targeting chimeras (PROTACs) (19-22); (III) molecular glue degraders (23-25); (IV) targeting Protein-DNA binding interfaces (26-28). The figure was created using the Gemini tool (https://gemini.google.com/).

Allele-specific covalent inhibitors

Allele-specific covalent inhibitors exploit unique amino acid residues introduced by cancer mutations to form an irreversible covalent bond that selectively inactivates the mutant protein by sparing the wild-type form (29). For example, the allele-specific covalent KRAS inhibitors sotorasib and adagrasib irreversibly bind to mutant cysteine residues at position 12 (KRAS G12C mutation), trapping the protein in its inactive GDP-bound state and preventing oncogenic signaling (18,29). The G12C mutation leads to a unique cysteine target which is not present in wild-type KRAS, allowing these drugs to selectively inhibit only the mutant protein by covalently binding to the switch II pocket (P2 pocket) (30,31). Both agents are U.S. Food and Drug Administration (FDA)-approved for KRAS G12C-mutated non-small cell lung cancer (NSCLC) and colorectal cancer, with adagrasib offering additional central nervous system penetration. Interestingly, despite the presence of the same mutation in different tumor types, activity of these inhibitors varies significantly across indications and rapid resistance development is commonly observed.

PROTACs

PROTACs are molecules with two ligands joined by a linker: one binds the target protein, while the other recruits an E3 ubiquitin ligase to promote ubiquitination and proteasomal degradation of the target (32). Unlike traditional inhibitors that block protein function, PROTACs catalytically eliminate the entire protein, enabling degradation of previously “undruggable” targets like transcription factors (TFs) and scaffold proteins with sustained effects at lower doses (33,34). Several PROTACs are now in clinical trials for cancer therapy, including ARV-471 for breast cancer, with advantages including overcoming drug resistance and achieving sub-stoichiometric efficacy (35).

Molecular glue degraders

Molecular glue degraders are small monovalent molecules that induce proximity between a target protein and an E3 ubiquitin ligase acting as a molecular bridge, initiating target ubiquitination and proteasomal degradation without the need for classical binding pockets (36-38). Unlike PROTACs which are bifunctional molecules with separate ligands for both target and ligase, molecular glues are compact, drug-like compounds that remodel protein surfaces to create neo-interactions, often exploiting pre-existing weak protein-protein affinities (39). Clinically approved examples include thalidomide, lenalidomide, and pomalidomide for multiple myeloma, with over 20 molecular glue degraders now in clinical trials targeting previously “undruggable” proteins like TFs (40-42).

Targeting protein-DNA binding interfaces

Strategies targeting protein-DNA binding interfaces employ small molecules that directly disrupt TF-DNA interactions through mechanisms including competitive DNA binding (e.g., DNA intercalators, groove binders, alkylating agents), direct binding to the TF’s DNA-binding domain to block DNA access, or stabilizing protein-DNA complexes as interfacial inhibitors (43-45). These approaches may overcome the traditional “undruggability” of TFs by exploiting sequence-specific DNA recognition sites or structural pockets in the DNA-binding domain, with successful examples including inhibitors of FOXM1, STAT3, AR, ERG, and MYC developed through computer-aided drug discovery (46,47). Recent preclinical advances include DNA-based PROTACs that use DNA oligonucleotides to recruit E3 ligases for degrading DNA-binding proteins, and compounds like FDI-6 that directly bind FOXM1 to displace it from genomic targets (48,49).

What are possible limitations and failures of such technological innovations in overcoming undruggable targets in the future?

The main issues of such new technologies to overcome undruggable targets in solid tumors are related to the risk of emerging resistance mechanisms, which depends on various biological determinants such as basement membrane, vasculature, immune cells and tumour microenvironment (50). Resistance can be both intrinsic and acquired and understanding these mechanisms is critical for the continued success of drugging undruggable targets (51).

For example, the introduction of KRAS G12C inhibitors in lung and colorectal cancer has demonstrated that resistance can arise through secondary KRAS mutations, activation of bypass signalling pathways, and phenotypic changes in tumor cells (14,52).

Comprehensive reviews further emphasize that as these new modalities are developed to drug undruggable targets, resistance still remains a major challenge. Mechanisms include target mutation, pathway reactivation, and tumor microenvironment adaptation, necessitating ongoing monitoring and rational combination approaches (50,53,54).

What are and will be very important undruggable targets in the future?

Juan Luiz Coelho-Silva et al.’s review (9) discusses numerous undruggable cancer targets but emphasizes that the most important future targets are those most common in human cancers: KRAS, MYC, and TP53. These genes drive many malignancies yet lack conventional ligand-binding sites for drug development (10,12,13). The following sections examine these frequently altered genes and outline emerging strategies to make them druggable.

MYC

MYC is one of the most commonly amplified oncogenes, present in ~70% of human cancers, but remains undruggable because of its disordered structure and nuclear localization. Emerging approaches—such as Omomyc (OMO-103), aptamer-based PROTACs, Bromodomain and Extra-Terminal (BET)/CDK9 inhibitors, and targeting the TRIB3-MYC axis—show promise for clinical MYC blockade and improved outcomes (55-58). Regarding targeting MYC with BET inhibitors, relevant associated issues include toxicity (59) and the emergence of resistance (60), which can be addressed by domain-selective BET inhibition and combination therapy to bypass adaptive resistance mechanisms (60-62).

KRAS (non-G12C mutations)

While KRAS G12C has been successfully targeted with sotorasib and adagrasib, other common mutations (G12D, G12V, G13D) lack the cysteine residue for covalent targeting and remain challenging. Zoldonrasib (RMC-9805) is an oral, mutant-selective KRAS G12D inhibitor designed to block the active form of KRAS by forming a tri-complex with cyclophilin A which prevents KRAS from signalling downstream (63). Early clinical data indicate promising activity in NSCLC with a manageable safety profile (64). Pan-KRAS degraders using heterobifunctional polymers (HYDRACs) show promise for targeting multiple KRAS alleles (65,66).

TP53 (mutant p53)

TP53 is the single most frequently mutated gene in human cancer, with mutations present in approximately 50% of all invasive tumors (67). TP53 is considered undruggable mainly because, as a nuclear TF, p53 lacks a typical druggable pocket and its tumor-suppressor role relies on protein interactions and DNA binding, not enzymatic action (67,68). Missense mutations lead to loss of function, dominant-negative effects (mixed tetramers with wild-type p53), and oncogenic gain-of-function traits that drive cancer growth and resistance (69,70). Still, efforts to reactivate mutant p53, such as with APR-246 in Phase III trials, aim to restore its tumor-suppressor activity (71-73). Besides reactivating wild-type p53, there are also strategies to directly target oncogenic mutant p53, including mutant-specific reactivation, promoting mutant p53 degradation, and blocking mutant p53’s gain-of-function pathways (74).

Ongoing methodical approaches to make more undruggable targets druggable

How new methodical approaches have the potential to make more undruggable targets druggable in the future will be discussed hereafter:

• Innovative drug modalities may broaden targeted therapies to proteins without typical binding sites or those involved in protein-protein interactions (10,65,75-77).
• In this context, programmable nucleic acid platforms leveraging RNA aptamers represent a highly versatile strategy capable of expanding the druggable proteome through high-affinity, conformation-specific binding. By acting as target-binding warheads in next-generation PROTACs (RNA-PROTACs) or serving as molecular decoys to disrupt TF complexes, these structured oligonucleotides effectively bypass the requirement for classical hydrophobic pockets. Consequently, integrating RNA aptamers into proximity-induced pharmacology offers an innovative strategy to counteract conventional small-molecule resistance mechanisms (78,79).
• Advances in computer-aided drug discovery and artificial intelligence (e.g., AlphaFold) could identify new ligandable sites and facilitate rational drug design for previously inaccessible targets (80,81). Furthermore, artificial intelligence could accelerate the identification of druggable targets by predicting 3D structures of proteins and compounds, identifying oncogenic allosteric driver mutations, and predicting allosteric druggable pockets (82).
• To minimize the risk of acquired resistance, particularly when targeting formerly ‘undruggable’ oncogenic drivers such as KRAS G12C, rational combination regimens that inhibit parallel or compensatory pathways, sequential treatment with agents of distinct mechanisms, and adaptive treatment strategies are essential (52-54,83,84).
• Continuous resistance mechanisms like target mutation, alterations in non-target proteins (e.g., E3 ligase components such as CRBN or VHL), bypass signalling, and changes in the tumor microenvironment drive the creation of next-generation inhibitors and shape combination treatment strategies to counteract resistance (52,54,83).
• Optimizing drug delivery systems (e.g., nanoparticles, antibody-drug conjugates) and improving pharmacokinetic properties are essential for maximizing efficacy and minimizing toxicity, especially for large or complex molecules like PROTACs (54,76).

Conclusive thoughts: where to go

The transition of ‘undruggable’ cancer targets to FDA- and European Medicines Agency (EMA)-approved therapies is underway, revolutionizing clinical practice and patients’ outcomes. Nevertheless, many questions remain unanswered.

Table 1 ranks current strategies for targeting “undruggable” proteins by weighing their strengths, limitations, clinical application and finally the future potential. Here, PROTACs are a leading platform in clinical trials for diverse targets, though their use is limited by pharmacological issues. Molecular glue degraders and allele-specific covalent inhibitors are less prominent, with narrow therapeutic windows and resistance concerns. Protein-DNA interface strategies are mainly preclinical, facing low selectivity and limited validation.

Relevant databases listed in Table 1 facilitate in silico drug design for degrader and covalent inhibitors. Covalent inhibitor discovery is supported by CovalentInDB 2.0 offering AI-based cysteine profiling and a 2-million-compound screening library for targeting beyond KRAS G12C. PROTACs feature the most mature ecosystem: PROTAC-DB 3.0 provides clinical pharmacokinetics, and TPDdb covers emerging modalities like Lysosome-Targeting Chimeras. For molecular glues, MGDB catalogs 7,396 compounds with ADMET profiles, while MGTbind uniquely provides AlphaFold 3-generated ternary structures. Conversely, protein-DNA interface strategies rely on general repositories like the Protein Data Bank and AI tools, reflecting their earlier developmental stage.

Coelho-Silva et al.’s review (9) ‘Targeting “undruggable” cancer proteins: pharmacological challenges and emerging strategies’, concludes that notable progress is being made in three main areas:

• Unlocking the “undruggable” targets: Beyond “flat surfaces”, the main challenge lies in the complexity of drug-target interaction and drug-target binding affinity. Unified modeling of these interactions can help overcome historic barriers by improving how we represent molecular recognition (85). Emerging strategies such as allele-specific covalent inhibitors, PROTACs, molecular glue degraders, and protein-DNA interface targeting are progressively expanding the druggable target space in human cancer, transforming previously inaccessible genes and their oncoproteins into viable therapeutic targets.
• Expanding therapeutic options for high-unmet-need malignancies: These novel approaches hold particular promise for tumor entities with historically dismal outcomes, as well as for rare cancers where conventional drug development has been limited by small patient populations and a lack of actionable targets. To illustrate this approach, three distinct human malignancies of epithelial, lymphatic, and mesenchymal origin are highlighted below:
  • Pancreatic ductal adenocarcinoma (epithelial): Has the lowest 5-year OS among major malignancies (~10–12%), with ~80% presenting as advanced or metastatic (86). Driven by KRAS alleles G12D (~43%), G12V (~34%), and G12R (~17%). Clinical evaluation of the KRAS G12D inhibitor MRTX1133 and pan-RAS inhibitor RMC-6236 marks the first milestone in directly targeting this driver (87,88).
  • Triple-class refractory multiple myeloma (lymphatic): Patients resistant to proteasome inhibitors, immunomodulatory drugs (IMiDs), and anti-CD38 antibodies have a dismal prognosis, with a median OS of ~10–19 months and PFS of ~3 months (89). To bypass IMiD resistance, next-generation molecular glues (mezigdomide, iberdomide) potently degrade IKZF1/3 and are in Phase 1–3 trials (90-92).
  • Ewing sarcoma (mesenchymal): Fusion-driven sarcoma where 5-year OS drops from 65–75% in localized disease to <30% in metastatic and <10% at 48 months post-recurrence (93,94). To target the driving TF, novel TF-PROTACs use DNA oligonucleotides as decoys to recruit E3 ligases for proximity-induced EWS-FLI1 degradation (95,96).
• Paving the way for next-generation drug design: Continued innovation—driven by AI-assisted molecular design, expanding online databases, and mechanistic insights into resistance pathways—is expected to overcome acquired resistance to current therapies and unlock entirely new classes of therapeutics against targets that remain undruggable today.

Acknowledgments

The authors thank Suki Tang for the kind invitation to prepare this editorial. The authors would also like to thank OpenEvidence (https://www.openevidence.com/) for conducting the literature search and the Gemini tool (https://gemini.google.com/) for generating the figure. Following the use of these tools, the authors reviewed and edited the content as necessary and take full responsibility for the final published article.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-0807/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-0807/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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