Traditional small molecule inhibitors work by blocking a protein’s active site to modulate its function. But many disease-driving proteins lack such accessible binding pockets or participate in complex protein–protein interactions that are notoriously difficult to disrupt. These “undruggable” proteins — long considered out of reach — comprise a vast portion of the proteome and are implicated in a wide array of diseases, from cancer to neurodegeneration to immune disorders.
Targeted protein degradation (TPD) is transforming this paradigm. Rather than attempting to inhibit a protein's activity, degraders recruit cellular machinery — specifically E3 ubiquitin ligases, the enzymes responsible for tagging proteins for destruction via the ubiquitin–proteasome system — to mark the target protein for destruction via the proteasome. This approach has the potential to eliminate proteins entirely, overcoming limitations of occupancy-based inhibition and offering prolonged pharmacodynamic effects with transient dosing.
Two key modalities dominate the TPD space: bifunctional molecules like PROTACs (proteolysis-targeting chimeras), which tether a target protein to an E3 ligase; and molecular glues, smaller molecules that stabilize or induce interactions between proteins and ligases to trigger degradation. These technologies open the door to targeting transcription factors, scaffolding proteins, and other classes previously beyond the reach of conventional drugs.
Biopharma has taken notice. Recent years have seen an explosion of partnerships and acquisitions as companies race to establish platforms capable of designing potent, selective degraders that can be delivered orally and reach diverse tissues. Still, the field is in its early innings, with major challenges — including E3 ligase selectivity, tissue targeting, and resistance mechanisms — yet to be fully solved.
Against this backdrop, a group of young biotech companies are emerging with novel platforms, ligase recruitment strategies, and drug candidates that aim to push TPD into clinical and commercial reality. Here are five to watch — Plexium, Nurix Therapeutics, Amphista Therapeutics, Kymera Therapeutics, and Captor Therapeutics — each offering a unique perspective on the evolving science and therapeutic potential of protein degradation.
Plexium: Advancing Monovalent Degraders and Molecular Glues
Plexium, headquartered in San Diego, is building a next-generation platform for targeted protein degradation that moves beyond the classical PROTAC paradigm. While most degraders in development are bifunctional molecules that link a protein of interest to an E3 ubiquitin ligase, Plexium’s innovation lies in its ability to discover and optimize monovalent degraders and molecular glues — small molecules that engage endogenous E3 ligases without the need for a bifunctional scaffold. This opens the door to more compact, drug-like, and orally bioavailable compounds that can access intracellular targets previously deemed undruggable.
At the core of Plexium’s approach is its proprietary cell-based screening platform, which leverages a highly multiplexed, functional phenotyping system capable of evaluating thousands of protein–ligase interactions in live cells. This enables not only the identification of hit compounds that induce degradation but also a deep mechanistic understanding of degrader selectivity, potency, and downstream biological effects. Importantly, the platform allows Plexium to uncover ligase–substrate interactions that may not be evident through biochemical assays alone — particularly critical in the discovery of molecular glue degraders, which often function through non-obvious mechanisms.
Plexium’s pipeline includes preclinical programs in oncology and neurodegeneration, two areas where conventional inhibition has fallen short. The company has shown particular interest in transcription factors, scaffolding proteins, and signaling adaptors — classes of proteins long considered undruggable owing to the absence of enzymatic activity or defined binding pockets. By degrading the protein entirely rather than blocking a single function, Plexium aims to achieve deeper and more durable responses.
The company has attracted high-profile collaborators, including Amgen, with whom it announced a strategic multi-target collaboration focused on cancer. This partnership not only validated Plexium’s discovery engine but also demonstrated industry confidence in the utility of monovalent degrader modalities.
What distinguishes Plexium in the crowded TPD space is its focus on functional outputs rather than static binding, a philosophy that reflects a shift from occupancy-driven drug design to one centered on cellular outcomes. In this way, Plexium is helping to rewrite the rules of what is chemically and biologically possible in protein modulation.
As the field races to overcome limitations of size, selectivity, and delivery associated with traditional PROTACs, Plexium’s elegant, ligase-focused discovery platform positions it as a nimble and forward-thinking leader in the quest to unlock the undruggable proteome.
Nurix Therapeutics: Harnessing E3 Ligases for Degrader Therapies
Nurix Therapeutics, based in San Francisco, is one of the earliest and most advanced players in the TPD space, with a focus on building a fully integrated drug discovery and development platform centered on modulating E3 ligases. What sets Nurix apart is its dual-pronged strategy: not only does it develop small molecule degraders to eliminate disease-driving proteins, but it also creates E3 ligase inhibitors and ligands to enhance or redirect ubiquitination pathways.
At the heart of Nurix’s innovation is its proprietary DELigase™ platform, which combines DNA-encoded libraries (DELs) comprising billions of compounds with artificial intelligence (AI) and structural biology to identify high-affinity ligands for E3 ligases and their substrates. This platform enables the rational design of both bifunctional degraders (akin to PROTACs) and more sophisticated, next-generation molecules that either enhance or reprogram the ubiquitin machinery.
Nurix’s pipeline includes clinical and preclinical programs spanning hematologic malignancies, solid tumors, and autoimmune diseases. Its most advanced asset, NX-2127, is a bifunctional degrader of Bruton's tyrosine kinase (BTK) that also modulates the transcription factor IKZF1. This molecule is currently in phase I clinical trials for B cell malignancies, targeting cancers resistant to conventional BTK inhibitors. Nurix also has NX-5948, an orally bioavailable BTK degrader with brain-penetrant properties, positioning it for diseases like central nervous system lymphoma.
In addition to its internal pipeline, Nurix is pushing the boundaries of delivery through its degrader–antibody conjugate (DAC) program, which marries the tissue-targeting capabilities of antibodies with the cell-penetrating power of small molecule degraders. This modality has the potential to bring TPD to targets that are difficult to reach systemically, such as those expressed in specific immune cell populations or tumor microenvironments.
Nurix has forged strategic partnerships with Sanofi and Gilead, both of which have committed hundreds of millions of dollars in upfront and milestone payments to co-develop novel degraders and ligase modulators. These alliances underscore the pharmaceutical industry’s recognition of Nurix’s deep E3 ligase know-how and validated platform.
While other players in the TPD field focus primarily on developing ligands to hijack a handful of well-characterized ligases (like CRBN or VHL), Nurix is expanding the repertoire by discovering new E3 ligases and building a library of bespoke ligase recruiters, broadening the chemical and biological space available for degradation. This capability may prove critical for designing degraders with improved tissue selectivity, resistance profiles, or the ability to degrade “tough” targets.
As the field matures, Nurix remains a scientific and strategic anchor in the space — at the intersection of ligase biology, AI-enabled discovery, and therapeutic ambition. Its commitment to both degradation and ligase modulation gives it a unique vantage point to influence the next generation of precision medicines.
Amphista Therapeutics: Developing Targeted Glues® for Protein Degradation
Amphista Therapeutics, headquartered in Cambridge, UK, is challenging the limits of traditional bifunctional degrader technology with a bold, differentiated approach to targeted protein degradation (TPD). Instead of designing large, dual-ligand PROTACs, Amphista is pioneering a next-generation class of small molecules it calls Targeted Glues® — rationally engineered monovalent compounds that catalyze the degradation of disease-relevant proteins by reprogramming endogenous degradation pathways.
Unlike PROTACs, which physically tether a target protein to an E3 ligase via two binding arms and often suffer from poor cell permeability and large molecular size, Amphista’s glues are low-molecular-weight compounds designed to engage both the target and the ligase interface through induced protein–protein interactions, offering improved pharmacokinetics, cell penetration, and tissue distribution. This innovation expands the chemical space for degraders and holds the potential to tackle a broader swath of proteins, including those considered inaccessible to bifunctional designs.
Amphista’s discovery engine is built on deep structural and mechanistic insights into E3 ligase substrate recognition, enabling the rational design of glues that promote novel, context-specific ternary complex formation. Their approach leverages proprietary chemistry and biology to explore ligases beyond the well-worn VHL and CRBN systems, seeking to exploit tissue-restricted or conditionally active E3 ligases that may enable more selective degradation and fewer off-target effects.
With a focus on oncology and neurodegenerative disorders, Amphista is advancing a pipeline of preclinical candidates designed to degrade proteins involved in transcriptional regulation, epigenetic control, and protein homeostasis. many of which have resisted inhibition by classical drug approaches. Its lead programs aim to address difficult-to-treat cancers with high unmet need and poor response to existing therapies.
Amphista has drawn significant validation from big pharma: in 2022, the company entered into a strategic collaboration with Bristol Myers Squibb, worth up to $1.25 billion in potential milestones, to co-develop targeted protein degradation therapies. This deal followed earlier collaborations with Roche and significant venture funding, including a $53 million Series B, reflecting investor confidence in Amphista’s potential to reshape the TPD field.
While companies like Plexium and Nurix work to expand degrader modalities through better screening and new ligases, Amphista’s platform represents a chemically elegant solution to the same problems — one that emphasizes small molecule drug likeness, oral bioavailability, and access to new biological space. The glue modality also carries potential advantages in manufacturability and intellectual property, given its monovalent design and novel mechanisms of action.
As the field seeks more efficient and scalable ways to develop degraders that can function across tissues and disease types, Amphista’s Targeted Glues offer a promising and differentiated route —pushing the boundaries of what’s druggable through degradation.
Kymera Therapeutics: Targeting Disease Drivers with Oral Degraders
Kymera Therapeutics, based in Boston, is one of the most clinically advanced and commercially ambitious biotechs in the targeted protein degradation space. The company is developing orally bioavailable small molecule degraders that modulate critical disease pathways by eliminating disease-driving proteins rather than merely inhibiting them. With a deep understanding of signaling biology and a strong focus on drug-like degraders, Kymera is helping to translate the promise of TPD into real-world therapeutic solutions.
Kymera’s proprietary Pegasus™ platform is built on three pillars: rational target selection, advanced degrader chemistry, and predictive pharmacology. This integrated approach allows the company to identify proteins whose degradation could deliver superior therapeutic outcomes compared to inhibition alone, and then to design bifunctional molecules that can effectively engage E3 ligases to mark those proteins for destruction. Importantly, Kymera has placed particular emphasis on developing orally bioavailable, systemically distributed degraders, a major challenge in the field given the size and complexity of PROTAC molecules.
The company’s pipeline spans immunology, oncology, and inflammatory diseases, with several programs in or approaching clinical trials. Among the most closely watched is KT-474, a first-in-class IRAK4 degrader being developed in partnership with Sanofi for the treatment of atopic dermatitis and hidradenitis suppurativa. By degrading IRAK4 — an upstream signaling node in TLR and IL-1 pathways — KT-474 aims to disrupt both innate immune activation and cytokine signaling more broadly than inhibitors alone.
Kymera is also advancing KT-621, an oral STAT6 degrader for asthma and other TH2-mediated inflammatory diseases, and KT-413, a dual-targeted degrader that simultaneously eliminates IRAK4 and Ikaros (IKZF1), a transcription factor implicated in B cell malignancies. This dual-degradation strategy underscores Kymera’s belief that eliminating multiple cooperating drivers can produce synergistic effects in complex diseases.
What differentiates Kymera is its strategic balance of depth and breadth. The company has demonstrated that TPD can yield small molecule therapeutics with the convenience, tissue penetration, and pharmacokinetics of traditional oral drugs while providing more complete suppression of disease targets. Its robust medicinal chemistry capabilities and proprietary linker technology allow Kymera to fine-tune the formation and stability of ternary complexes, improving potency and selectivity.
The biotech has secured major partnerships, most notably with Sanofi and Vertex Pharmaceuticals, helping to de-risk its pipeline and accelerate development in both immunology and cancer. These alliances reflect growing confidence not just in Kymera’s individual assets but in its ability to consistently deliver drug-like degraders across multiple indications.
In a field where some companies are just entering the clinic, Kymera stands out for clinical maturity, platform depth, and commercial vision. Its success will help set the bar for what protein degradation can deliver, not only scientifically but as a new drug class ready for broad patient impact.
Captor Therapeutics: Utilizing Optigrade™ for Precision Degradation
Captor Therapeutics, a rising biotech with research hubs in Switzerland and Poland, is carving out a distinctive position in the TPD landscape by focusing on precision degradation through rational design. With its proprietary Optigrade™ platform, Captor is engineering small molecule degraders to target disease-driving proteins that have long resisted conventional drug development approaches. The company’s geographic footprint in Central Europe also highlights the growing global reach of innovation in protein degradation, beyond traditional biotech hubs.
Captor’s platform emphasizes structure-guided degrader optimization, combining computational chemistry, X-ray crystallography, and functional screening to design degraders with exceptional selectivity and drug-like properties. A key tenet of their approach is the strategic pairing of specific targets with optimal E3 ligases, maximizing degradation efficacy while minimizing off-target effects. This ligase-target matchmaking, informed by structural biology and cellular context, enables the design of tailored molecules for challenging indications.
The company is advancing a pipeline primarily focused on oncology and autoimmune disease, with several programs progressing through IND-enabling studies. Among its lead candidates are degraders targeting GSPT1, a translation termination factor with emerging relevance in hematologic malignancies; SALL4, a stem cell transcription factor implicated in drug resistance and hepatocellular carcinoma; and NEK7, a kinase involved in inflammasome activation and inflammatory disease pathogenesis. These targets reflect Captor’s ambition to expand TPD into both well-validated and frontier biology.
Captor is also developing degraders designed to overcome resistance mechanisms associated with classical inhibition. By fully degrading the target protein — including any non-catalytic scaffolding or regulatory functions — Captor’s candidates may deliver deeper and more durable responses, especially in cancers driven by oncogenic protein–protein interactions or aberrant transcriptional regulation.
Though still preclinical, the company has drawn attention for its high-value therapeutic targets and platform innovation. In 2021, Captor became one of the few TPD-focused companies to go public in Europe, raising capital to accelerate development of its Optigrade-derived programs. The company also participates in multiple European R&D consortia, reflecting its deep academic ties and commitment to translational research.
While firms like Nurix and Kymera lead in clinical-stage degraders, Captor stands out for its high-potential targets and strategic focus on structural precision. Its ability to craft selective degraders tailored to specific biological contexts could yield first-in-class therapeutics for difficult-to-treat diseases—and bring TPD innovation from Europe into the global spotlight.
As the race to drug the undruggable continues, Captor Therapeutics brings both scientific rigor and strategic originality to the frontlines of protein degradation.