Expanding the Therapeutic Toolbox: New Modalities for Modern Drug Hunters
Paradoxical MAPK Activation: The Dabrafenib Case Study
Dabrafenib marked a major step in targeted therapy, selectively inhibiting BRAFV600E kinase (IC₅₀ ≈ 0.65 nM) with greater potency than BRAFWT (Figure 1). However, its promise came with a caveat: in cells with activated RAS and wild-type BRAF, paradoxical MAPK activation can occur via RAF dimerization, potentially promoting tumor growth or resistance [1-3]. This limitation prompted the development of new strategies to improve selectivity and pathway fidelity.
Figure 1. Dabrafenib Profile and BRAF Kinase Structure (PDB: 5CSW)
To counter this, next-generation BRAF inhibitors, such as PLX8394, tovorafenib, belvarafenib and others were designed to disrupt RAF dimerization or selectively target mutant BRAF without activating wild-type signaling (Figure 2) [4-5].
Figure 2. Next-Generation BRAF Inhibitors Designed to Avoid Paradoxical MAPK Activation
More recently, a fundamentally different strategy has emerged: targeted protein degradation. PROTAC degraders like SJF-0628 and CRBN(BRAF)-24 go beyond blocking kinase activity, instead recruiting E3 ubiquitin ligases to remove BRAFV600E entirely. In preclinical models, this approach not only achieves potent and selective degradation of mutant BRAF but also avoids the paradoxical activation seen with traditional inhibitors [6, 7].
Figure 3. SJF-0628: BRAF-Targeting PROTAC
This shift - from inhibition to elimination - reflects a broader evolution in drug discovery: the rise of new therapeutic modalities, where controlling a protein’s fate offers new ways to tune cellular signaling with greater precision.
Therapeutic Modalities: Classification Frameworks
In the context of drug discovery, a modality refers to the molecular form/fundamental mechanism by which a therapeutic engages and modulates its biological target [8, 9, 10, 11].
The classification of drug modalities has expanded beyond traditional small molecules to encompass a wide range of structural and mechanistic innovations, including peptides, proteins, monoclonal antibodies, RNA-based drugs, antibody-drug conjugates (ADCs), targeted protein degraders (e.g., PROTACs, molecular glues), gene therapies, and cell therapies like CAR-T cells.
Various frameworks have been proposed to organize this growing diversity. For instance, Laurel Oldach, in “How to choose a disease-fighting molecule,” broadly grouped new modalities into small molecules, such as inhibitors and degraders, and biologics, including antibodies, RNA therapeutics, and cell or gene therapies [12]. While the boundaries between these categories are not always distinct, this dichotomy provides a useful lens for drug developers.
In another approach, Valeur et al. categorized emerging modalities by their mechanisms of action, into groups such as protein-protein interaction (PPI) stabilization, protein degradation, RNA downregulation/upregulation, and multivalent/hybrid strategies [9].
Table 1. Summary of Emerging Therapeutic Modalities Categorized by Mechanism of Action (Adapted from Valeur et al., 2019)
Additionally, Blanco and Gardinier proposed a dual framework: one classifying modalities by chemical structure and MOA, and another aligning them with specific biological use cases, for example, using RNA therapeutics for gene silencing or ADCs for targeted cancer treatment [8].
Table 2. Classification of New Chemical Modalities (Adapted from Blanco, M.-J.; Gardinier, K. M.)
Meanwhile, Liu and Ciulli offered a functional classification of proximity-based modalities, organizing them by therapeutic goals such as degradation, inhibition, stabilization, and post-translational modification, and further distinguishing them by structural complexity (monomeric, bifunctional, multifunctional) [11].
Table 3. Classification of Proximity-Based Modalities by Mechanism and Structure (Adapted from Liu, X., & Ciulli, A.)
Collectively, these classification systems reflect the increasing complexity and strategic versatility of modern therapeutics, emphasizing the importance of selecting the right modality to match the biological target and clinical need.
Therapeutic Modality Selection: Frameworks and Practical Considerations
Today, we are in an especially exciting era for drug developers, as the therapeutic toolbox has expanded far beyond traditional small molecules. While small molecules remain a cornerstone of drug discovery, their limitations - such as limited specificity, off-target effects, and inability to target certain proteins - have prompted a shift toward novel therapeutic modalities, each offering distinct strengths and weaknesses [13].
For example, monoclonal antibodies provide exceptional specificity and long half-lives but are limited to extracellular targets and typically require injection [14]. RNA-based therapies offer gene-level control but depend on advanced delivery systems and carry risks of immune activation [15], while gene and cell therapies hold curative potential yet come with high complexity, regulatory hurdles, and safety considerations [16]. Modalities like PROTACs and molecular glues offer the ability to degrade or modulate previously “undruggable” proteins, though challenges with size, delivery, and design remain [17, 20].
There is growing recognition that these newer approaches can complement or even outperform small molecules in specific scenarios. However, selecting the optimal strategy remains a complex and strategic process, shaped not only by biology and chemistry but also by practical considerations such as modality maturity, regulatory precedent, and internal expertise.
Frameworks like the one proposed by Blanco and Gardinier provide structure for this decision-making by focusing on three key pillars: establishing a strong link between the target and human disease, understanding the biological pathway and mechanism of action, and matching the target’s properties with a modality capable of effectively reaching and modulating it [8] (Figure 4).
Figure 4. Three Pillars of Therapeutic Modality Selection (Adapted from the framework proposed by Blanco and Gardinier.)
This structured approach is further enriched by real-world insights, as highlighted by Laurel Oldach in Chemical & Engineering News, where experts emphasize that modality selection also depends on iterative hypothesis testing, data availability, target druggability, delivery challenges, and alignment with team expertise and organizational strengths [12].
When all the essential elements align - deep understanding of the target, scientific expertise, creativity, organizational capabilities and others - breakthroughs become possible. A striking example is Revolution Medicines, where scientists have combined modalities in smart, strategic ways to complement insights from molecular and structural biology.
Their approach, the Tri-Complex Inhibitor (TCI) platform, integrates the structural advantages of macrocycles with the mechanistic versatility of molecular glues to target mutant RAS proteins, long considered “undruggable.” The TCI mechanism forms a stable tri-complex between the mutant RAS protein, the chaperone cyclophilin A, and a small-molecule inhibitor. For instance, RMC-9805, a macrocyclic molecular glue designed to target KRASG12D, stabilizes the interaction between GTP-bound KRAS and cyclophilin A- selectively locking the mutant in an inactive state while sparing the wild-type form. As a macrocycle, it benefits from high binding affinity and favorable pharmacokinetics [18, 19, 21] .
Figure 5. Selective and Multi-Selective RAS(ON) Inhibitors
Other TCI compounds include RMC-6291, a covalent inhibitor selective for KRASG12C, and RMC-6236, a noncovalent, multi-RAS inhibitor now in Phase 3 trials (Figure 5). These agents exemplify how integrated modality design can expand the druggable proteome and improve treatment precision and offer a path forward where traditional inhibitors have failed.
While macrocycles such as RMC-6291 are emerging as powerful tools in drug discovery, particularly for targeting protein–protein interactions and other challenging cases like RAS, they can be very difficult to synthesize. Advances in retrosynthesis now allow chemists to design more efficient and reliable synthetic routes. At Chemical.AI, we have shown how the ChemAIRS platform can be applied to the retrosynthetic analysis of RMC-6291, illustrating how AI-driven planning can support the practical realization of these complex molecules.
Modality as a Strategic Lever in Modern Drug Discovery
The evolution from simple enzyme inhibitors to complex modalities like PROTACs, RNA therapeutics, and tri-complex inhibitors reflects a profound shift in how we approach drug development. No longer is the question simply can we inhibit this target? - today, the real question is what’s the optimal way to modulate this biology, for the right patient, with the greatest precision?
The case of dabrafenib and paradoxical MAPK activation highlights the limits of conventional inhibition and the value of modality innovation. As the therapeutic toolbox expands, so too must our decision frameworks. The most successful biotech innovators will not only harness new modalities but will strategically align them with disease biology, target characteristics, and platform strengths.
In this new era, modality selection is a foundational strategic decision, capable of opening up new biological space, overcoming historic resistance mechanisms, and ultimately improving patient outcomes.
Those who master this shift, combining deep scientific understanding with modular, forward-looking modality strategies, will define the next generation of precision medicines.
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