Undruggable Drugs

Episode Summary

Executive Summary: Jay Bradner explains that “undruggable” targets are mostly those not addressable by traditional small-molecule methods, not truly impossible targets. He highlights how new modalities—especially allosteric inhibition, molecular glues, and targeted protein degradation—are expanding what can be therapeutically reached, while stressing that rigorous biology, delivery, and patient-centered development remain essential.

Main Topics: What “undruggable” means (Priority: 5/5): The term describes proteins, protein families, or RNA that cannot yet be targeted by conventional drug discovery methods, often because they lack obvious pockets or workable binding sites. Why biology can be well understood but still hard to drug (Priority: 5/5): Bradner emphasizes that many targets are biologically validated and disease-relevant, but historical drug discovery paradigms have not provided a practical way to intervene. Allosteric inhibition as a breakthrough (Priority: 5/5): The SHIP2 phosphatase example shows how screening for non-active-site binders uncovered a new way to inhibit an enzyme once considered effectively inaccessible. Molecular glues and targeted protein degradation (Priority: 5/5): The conversation explores molecules that force new protein-protein interactions or recruit proteins to the ubiquitin-proteasome system, enabling removal of disease-causing proteins rather than mere inhibition. Expanded therapeutic modalities (Priority: 4/5): The episode surveys the broader toolset now available—small molecules, antibodies, bispecifics, cell therapies, gene therapies, RNA, CRISPR, base editing, and prime editing—and how modality must match biology. Translational and manufacturing realities (Priority: 4/5): The discussion stresses that effective medicines must be deliverable, manufacturable, and accessible globally; some therapies are more like medical procedures than pills. Novartis’ research model and long horizon (Priority: 4/5): Bradner describes a translational basic-research model that commits to long-term discovery, patient-relevant proof of concept, and learning from clinical use to inform next-generation medicines.

Key Arguments: “Undruggable” is not a permanent biological fact; it often means undruggable by the old paradigm of active-site small molecules. Many disease drivers, including transcription factors and phosphatases, are biologically validated yet historically difficult to target, so dogma—not biology alone—has limited progress. Allosteric sites can provide entirely different intervention points that are invisible to conventional structural assumptions focused only on crystalized active sites. The SHIP2 phosphatase breakthrough came from screening full-length protein versus truncated enzyme and keeping only compounds that depended on the intact protein context. Molecular glues can either stabilize a nonfunctional protein conformation or bring two proteins together to alter disease biology. Targeted protein degradation can eliminate an entire protein’s function, which may overcome resistance and expand druggability beyond enzymes to scaffolding proteins. Advances in chemistry, structural computation, cell systems, stem-cell-derived models, and data science are enabling these new modalities. Successful development requires pairing the right biological target with the right therapeutic modality and considering delivery, manufacturing, and real-world patient access from the outset. Some promising therapies will still look like conventional pills, but others will require complex interventions such as viral injections, bone marrow transplantation, or ex vivo cell manufacturing. Drug discovery should be translational from the beginning, with early clinical trials used to find the right patient population and refine the medicine. Data Points: Novartis protein targets degraded: more than 50 or 60 proteins - Bradner cites this scale as evidence that targeted protein degradation is broadly applicable. Drug discovery horizon: 10 or 15 years - He notes that some pivotal targets may require a decade or more of sustained research to reach patients. Car T therapy manufacturing: made for one patient at a time - Used to illustrate the extreme personalization and complexity of living therapies. Transcription factor example: MIC - Described as the most commonly activated gene in all of cancer and still not successfully drugged. High-throughput screening approach: 2 screens - One screen used full-length phosphatase; the other used the active enzyme pocket alone to isolate allosteric hits. Initial hit count: 1,000 hits - Reported from the phosphatase screening campaign before narrowing to two relevant molecules. Targeted protein degradation discovery timeline: over the last five years - Referenced as the period since the first major discovery reported in Science Magazine. Scientific workforce at NIBR: 5,600 drug hunters - Used to describe the scale and scholarly intensity of the Novartis Institute for Biomedical Research.

Pivotal Quotes: "In the fullness of time, there may be no such thing as an undruggable target when you take in sort of the full armamentum of different modalities that we might go after a specific target." — Jay Bradner: Summarizing the central thesis that modality innovation can erase the undruggable category. "We threw out all the molecules that would inhibit the active site and kept only molecules that worked when these other sites were present, called allosteric sites." — Jay Bradner: Describing the key experimental insight behind the SHIP2 phosphatase inhibitor. "This is a white blood cell taken from the patient, infected with a virus, expressing a novel gene, expanding and growing inside of patients as a living therapy as it kills cancer cells." — Jay Bradner: Explaining CAR T as an example of a radically different therapeutic modality.

Implications: Drug discovery is moving from “can we bind this target?” to “what modality best rewrites the biology?” This expands what can be treated, but also raises new challenges in delivery, manufacturing, and access.