Unlocking the Undruggable: How Biotechnology Is Rewriting Drug Discovery

For decades, drug discovery followed a familiar path: identify a disease-driving protein, locate a surface pocket, and design a molecule to fit. This strategy produced breakthroughs—from imatinib to dozens of kinase inhibitors—but also exposed a major limitation. Many crucial proteins lacked druggable pockets or resisted traditional therapeutics.

Targets like KRAS, BCL-2, transcription factors, and intrinsically disordered proteins (IDPs) were long considered undruggable. Today, advances in biotechnology, structural biology, and computational modeling are revealing that these proteins are not undruggable—only difficult.

The wall is cracking.

From Phenotypic Screening to Targeted Therapy

Drug discovery began with phenotypic screens: testing crude extracts and observing biological effects. With molecular biology, the field shifted toward target-based drug design, enabling precise interventions against receptors, channels, and enzymes with clear pockets. Biologics expanded the toolbox further but still covered only ~2% of the human proteome.

The rest—transcription factors, flexible proteins, broad PPIs—remained inaccessible.

Now, computational methods, structural insights, and novel modalities are pushing the boundaries of what can be targeted.

Why Some Targets Resist

So-called undruggable targets present specific challenges:

• Selectivity problems: Highly conserved active sites make avoiding off-target effects difficult.
• Flexibility: IDPs refuse to conform to traditional binding models.
• Protein–protein interfaces: Flat, diffuse surfaces lack obvious cavities.
• Chemical constraints: Polar, solvent-exposed surfaces clash with drug-like property requirements.

Despite this, drugs such as venetoclax (BCL-2 inhibitor) and sotorasib (KRAS G12C) prove these challenges can be overcome.

Repurposing as a Shortcut

Drug repurposing offers a fast, cost-effective strategy:

• Avoids early safety and manufacturing hurdles
• Represents one-third of recent FDA approvals
• Generates ~25% of pharmaceutical revenue

Classic examples—sildenafil, propranolol, aspirin—show the power of reinterpreting drug effects.
Today, AI-driven transcriptomic matching, EHR mining, and network pharmacology are transforming repurposing from luck into strategy.

Challenges remain (limited IP protection, restricted data access), but opportunities in rare diseases, pandemics, and personalized medicine keep repurposing at the center of innovation.

Expanding the Toolbox: New Biotechnologies

What truly reshapes the undruggable landscape is the emergence of new therapeutic modalities:

• PROTACs (Protein Degraders): Redirect the cell’s degradation machinery to eliminate disease-driving proteins.
• Multispecific drugs: Engineer hybrid molecules or antibodies with multiple targeting functions.
• Nucleic acid therapeutics: RNA, antisense, siRNA, and gene-editing tools that modulate expression directly.
• Peptidomimetics: Molecules mimicking protein structures to bind difficult PPIs or flat surfaces.

Breakthroughs highlight the potential:

• Venetoclax broke into BCL-2’s stubborn PPI interface.
• Sotorasib exploited a newly discovered KRAS pocket.
• HIF-2α inhibitors targeted a transcription factor once deemed inaccessible.
• Computational peptide design (e.g., Peptilogics’ PLG0206) showcases the growing power of virtual design and optimization.

Industry Growing Pains

Despite technological leaps, the industry faces paradoxes:

• Drug approval rates stagnated in the 2000s (~12% from Phase I to approval).
• Failures stem from lack of efficacy, toxicity, and poor pharmacology.
• Outsourcing and academia–industry partnerships help, but inefficiencies persist.

Modern drug discovery must address not only what to target but how to streamline the entire pipeline.

Streamlining the Path Forward

New strategies aim to modernize clinical development:

• Adaptive trial designs
• Biomarker-driven recruitment
• AI-guided study planning
• Use of real-world evidence
• Network pharmacology for multi-target understanding

Regulatory pathways like orphan drug, fast-track, and breakthrough therapy designations further accelerate translation.

A New Era for the “Undruggable”

The frontier is shifting.

What used to be considered undruggable is now simply challenging. With:

• Repurposing
• PROTACs
• Multispecifics
• Nucleic acid therapeutics
• AI-designed peptides
• High-resolution structural biology
• Computational screening at scale

the drug-discovery world is steadily expanding into previously unreachable biology.

The age of the undruggable is ending.
What follows is a landscape where creativity, computation, and biotechnology converge—and fewer targets remain truly out of reach.

Source:
DrugBank. Unlocking Undruggable Targets: Biotechnology’s Role in Expanding Drug Discovery. 2024.