Revolutionizing Pharmaceutical Development! From "Effective Molecules" to "Designed Systems" in Drug Development

The "Second Act" of Small Molecule Drugs Has Begun—Complex Molecules Are Transforming Drug R&D

In the pharmaceutical industry, the prevailing view has long been that "small molecule drugs are a mature field, and the next stars will be large molecules and new modalities like antibodies, cell therapy, gene therapy, and RNA medicines." Indeed, the growth of biopharmaceuticals has been remarkable, with antibody drugs and cell and gene therapies achieving groundbreaking results in areas such as cancer, autoimmune diseases, and rare diseases.

However, small molecule drugs are once again gaining attention. And it's not just a simple matter of "inhibiting enzymes with low molecular weight" as in the past. Today's small molecule drug discovery involves not just stopping proteins but degrading them. It involves forming covalent bonds with specific amino acid residues, not just temporarily binding to targets. It involves designing drug efficacy by observing the behavior of entire intracellular networks, not just targeting a single target.

In other words, small molecules are no longer "old drug discovery methods." Instead, they are returning to the forefront of pharmaceutical R&D by incorporating the latest technologies such as AI, structural biology, omics analysis, mass spectrometry, flow chemistry, biocatalysis, robotics, and automated reaction optimization.

The content announced by WuXi AppTec succinctly reflects this change. The company points out that modern small molecule drugs have become structurally more complex, and it is becoming difficult to respond with the traditional model of separate drug discovery, development, and manufacturing, especially in programs like targeted protein degradation drugs, covalent inhibitors, and next-generation kinase inhibitors.

From "Binding Drugs" to "Designed Function Drugs"

Traditional small molecule drug discovery focused on finding compounds that bind with sufficient strength and selectivity to proteins involved in diseases. Compounds fit into the pockets of target proteins, inhibiting enzyme activity or signal transduction. The basic pharmacological action was akin to finding a "key that fits the lock."

Of course, this concept remains important. Many drugs are still designed based on this principle. However, in new small molecule drug discovery, simply binding is not enough. Considerations must include how the drug interacts with the target over time, which proteins it brings together within the cell, whether it induces target degradation, whether it has irreversible effects, and what changes it causes in downstream signal networks.

For example, in the field of targeted protein degradation drugs, known as PROTACs or molecular glues, it is not enough for the drug to just bind to the target protein. It must bring the target protein and E3 ligase close together, allowing the cell's inherent protein degradation system to recognize the target. In this case, the shape, stability, spatial arrangement, and linker length and flexibility of the ternary complex formed by the target, drug, and E3 ligase are directly linked to drug efficacy.

The same applies to covalent inhibitors. In the past, covalent drugs were sometimes avoided due to concerns about off-target toxicity. However, in recent years, precise targeting of specific residues on target proteins has advanced, leading to a reevaluation as a means to achieve long-acting effects and high target occupancy. Here, questions such as which residue to bind to, how much to suppress reactivity, whether to make it reversible, and how it is metabolized in the body become important from the exploratory stage.

Changes are also occurring in the field of kinase inhibitors. Merely strongly inhibiting a single target may allow cancer cells or disease networks to escape using alternative pathways. Therefore, recent kinase drug discovery requires more precise design of actions while observing the response of the entire intracellular network and resistance mechanisms.

Such drugs can no longer be advanced with the mindset of "finding a well-binding molecule and then considering manufacturing methods." The molecules themselves are complex, the expression of drug efficacy is complex, and manufacturing, analysis, and quality control also become complex.

The Issue of Drug Discovery Success Rates—Not Just Speed, but "How to Hit" Matters

One of the biggest challenges in pharmaceutical R&D is the high failure rate in clinical development. It is not uncommon for compounds that seemed promising in the early stages of drug discovery to fail to demonstrate the expected effects in animal or clinical trials. The reasons are varied: the target hypothesis was wrong, the selection of patient populations was inadequate, biomarkers were inappropriate, pharmacokinetics differed from expectations, toxicity or safety issues arose, or quality wavered during manufacturing scale-up. Drug discovery is not merely a "race to make compounds quickly," but a competition to "connect the right hypothesis to the right molecule and the right development plan."

WuXi AppTec also emphasizes this point. Technologies such as DNA-encoded libraries, fragment screening, direct-to-biology, mass spectrometry, spatial analysis, cell-type-specific analysis, flow chemistry, biocatalysis, and automated reaction optimization are individually very powerful. However, they do not generate sufficient value if they are isolated. Only when chemical synthesis, structural biology, computational modeling, translational biology, analytical science, and manufacturing technology are connected as a single flow can the success rate of complex small molecules be increased.

Here, the existence of CRDMO becomes important. CRDMO stands for Contract Research, Development, and Manufacturing Organization, which refers to organizations that contract and support research, development, and manufacturing. Traditionally, drug discovery exploration was done by Company A, process development by Company B, and manufacturing by Company C, with partners often divided by stage. However, in complex small molecules, such division becomes a risk.

The structure chosen in the exploratory stage can sometimes make later synthetic routes difficult. If initial analytical conditions are inadequate, impurity management can become an issue during scale-up. If manufacturing methods are only considered after candidate compounds are decided, significant setbacks can occur in the later stages of development. In other words, in complex small molecules, "we'll figure it out later" is not feasible.

The Era of Considering Manufacturing from the Early Stages

In pharmaceutical development, the exploratory and manufacturing stages are sometimes treated as separate worlds. Exploratory researchers focus on activity and selectivity, while manufacturing personnel focus on yield, reproducibility, impurities, cost, scale, and quality assurance. Both perspectives are essential, but the risk increases the longer the connection is delayed.

Especially for molecules like PROTACs, which have large molecular weights and complex linker structures, controlling polarity and flexibility is challenging. In covalent inhibitors, if reactivity is too strong, safety risks increase, and if too weak, sufficient efficacy cannot be achieved. In kinase inhibitors, selectivity, network effects, and responses to resistance mutations must be considered simultaneously. For such molecules, ease of synthesis, ease of analysis, stability, and manufacturing reproducibility affect the value of the candidate compound itself.

Therefore, process development should not start after candidate compounds are finalized but should be considered in parallel from the early stages of exploration. Which route makes impurity management easier? Which intermediates are prone to instability? Which steps become bottlenecks during scale-up? Which analytical methods can be used until the late stages of development? The earlier these decisions are made, the shorter the time to clinical entry and the lower the risk of setbacks.

What WuXi AppTec's announcement indicates is precisely the importance of this "consistency." If exploration, development, and manufacturing can share information across organizational boundaries, early decision-making can be more easily carried over to later processes. If multiple teams can operate under the same quality system, the need to relearn at each stage is reduced. This relates not only to shortening development periods but also to stabilizing quality.

On Social Media, the Perception Is That "Small Molecules Are Not Legacy"

Looking at reactions on social media, the widespread dissemination of this article itself is still limited. However, in discussions among pharmaceutical and biotech professionals, particularly on LinkedIn, views aligning with the article's claims are prominent.

One reaction is that "small molecules are not an old technology; they are being reinvented." While antibody drugs and cell therapies are in the spotlight, small molecules have strengths such as being easy to administer orally, easy to access intracellular targets, and easy to mass-produce. With new design concepts like PROTACs, molecular glues, covalent inhibitors, RNA targeting, and small molecule gene editing control, small molecules are evolving from "simple inhibitors" to "molecular-level control devices."

Another reaction is that "value is only realized when combined with AI and structural biology." Complex small molecules have a wide design space, and there are limits to optimizing them based solely on human experience. Predicting which linker is best, which stereochemical conformation is advantageous, and which target engagement strategy leads to biological outcomes requires computational models and high-quality experimental data. Therefore, themes like AI drug discovery, single-cell analysis, structural prediction, and lab automation are often discussed alongside small molecule drug discovery on social media.

On the other hand, there are cautious views. Complex molecules are attractive, but if manufacturing is difficult, it becomes a barrier to commercialization. Even if efficacy is strong, if the synthetic route is long, yield is low, and impurity management is difficult, issues of cost and supply stability arise. Especially in programs involving high-potency active pharmaceutical ingredients, safe handling facilities and containment technologies are also needed. In industry-related posts on social media, the "scientific appeal of new modalities" and the "practical issues of whether they can be made, mass-produced, and quality maintained" are often discussed simultaneously.

In this regard, the article is not just a technical trend introduction. Rather, it indicates that the axis of competition in drug discovery is shifting from "what kind of molecules to find" to "what kind of molecules to develop into a feasible form from which stage and how."

The Perspective Required for Pharmaceutical Companies and Biotechs

In the era of complex small molecules, what should pharmaceutical companies and biotechs reconsider? First, it is necessary to consider "which modality is optimal" from the target selection stage. It is important to comprehensively judge disease biology, target location, patient population, administration route, manufacturability, cost, and lifecycle strategy, rather than simply comparing which is superior among small molecules, antibodies, ADCs, RNA medicines, or cell therapies.

Second, it is necessary to incorporate the perspective of CMC, i.e., chemistry, manufacturing, and quality control, from the exploratory stage. This is not to reduce the freedom of researchers. Rather, it is to increase the success rate of bringing promising molecules to clinical and commercial stages. Sometimes, just a slight change in design early on can significantly reduce later manufacturing difficulty and impurity risk.

Third, data continuity becomes important. If structure-activity relationships, structural biology data, reaction conditions, analytical results, toxicity signals, and pharmacokinetic data obtained in exploration are not carried over to development and manufacturing, the same failures will be repeated. In complex small molecules, information discontinuity from research to manufacturing is likely to cause development delays.

Fourth, the criteria for choosing external partners also change. It is not enough to simply "be able to synthesize" or "have manufacturing capacity." In complex small molecules, the ability to consistently support exploration support, structural analysis, analysis, process development, scale-up, quality systems, and global supply is questioned. Especially for small biotechs, it is difficult to have all functions in-house, so the value of integrated CRDMOs tends to increase.

The Big Future Carried by "Small Molecules"

The appeal of small molecule drugs also lies in their ease of use for patients. Many small molecule drugs can be administered orally and are often easier to handle in terms of storage and distribution compared to biopharmaceuticals. The ability to access intracellular targets is also a significant advantage. While antibodies are strong against extracellular or membrane surface targets, small molecules have the potential to challenge a wider biological space, such as intracellular enzymes, transcription factors, protein-protein interactions, and RNA.

Of course, small molecules are not optimal for all diseases. Future pharmaceutical R&D will not be a binary opposition of small molecules versus large molecules, but an era of choosing the optimal modality according to the target and disease. In this context, small molecules are being redefined not as merely "traditional pharmaceuticals," but as flexible tools for controlling complex life systems.

The biggest message of this article is that in the development of complex small molecules, science, technology, manufacturing, quality, and data should not be considered separately. Understanding targets, designing molecules, synthesizing, analyzing, manufacturing, and ensuring quality—connecting all these processes from an early stage will determine the success of next-generation drug discovery.

Small molecules are small. However, their role is no longer small. Complex small molecules, combined with AI, automation, structural biology, and precise chemical design, are becoming the new battleground in pharmaceutical R&D. The future of drug discovery is expanding not only in large biopharmaceuticals but also in meticulously designed small molecules.

Source URL

Reprinted article "Complex Small Molecules Are Changing Drug R&D" published on Aktiencheck. Used for confirming article title, distribution date, and summary of WuXi AppTec's announcement.
https://www.aktiencheck.de/news/Artikel-Complex_Small_Molecules_Are_Changing_Drug_R_D-19884357

Original announcement: Press release by WuXi AppTec published on GlobeNewswire. Used for confirming points on complex small molecules, targeted protein degradation drugs, covalent inhibitors, kinase programs, and integrated CRDMOs.
https://www.globenewswire.com/news-release/2026/06/26/3318126/0/en/complex-small-molecules-are-changing-drug-r-d.html

Related industry reactions: Discussions on small molecule drug discovery on LinkedIn. Used for confirming reaction trends that small molecules are being re-evaluated in connection with TPD, covalent inhibitors, AI drug discovery, etc.
https://www.linkedin.com/top-content/innovation/advancements-in-medical-research/how-small-molecules-are-transforming-drug-development/

Background information: Convergence of small and large molecules, FDA approval trends, and trends in small molecule R&D such as PROTACs and RNA targeting.
https://www.drugdiscoverytrends.com/moving-beyond-the-binary-how-the-convergence-of-small-and-large-molecules-is-reshaping-pharmaceutical-rd/

Background information: Manufacturing difficulty of complex small molecules, increase in synthetic steps, high-potency active pharmaceutical ingredients, and the importance of value chain integration.
https://www.outsourcedpharma.com/doc/emerging-trends-in-complex-small-molecule-drug-production-0001/