Small Molecule Drugs: New Trends in Targeting Large Molecules

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Over the past century, small molecule drugs have been the cornerstone of the pharmaceutical industry. Defined as organic compounds with a low molecular weight (less than 1000 Da), they offer several advantages for therapeutic use: most can be administered orally and can cross cell membranes to reach intracellular targets. They can be designed to interact with biological targets through various modes of action, and their distribution can be further customized, for example, to allow systemic exposure cross blood-brain barrier.

As biologics like Humira, Keytruda, and Stelara continue to break sales records, pharmaceutical companies are increasingly facing the choice between small molecules and biologics in drug development. Despite the significant achievements of biologics, small molecule drugs still dominate the industry. With technological advancements, small molecule drugs are continually creating new development conditions. Let’s take a comprehensive look at small molecule drugs.

Advantages and Challenges in Small Molecule Drug Development

Small molecule drug development remains mainstream in the field of drug research and development, with numerous advantages and challenges.

Advantages:

  • Small molecule drugs are easy to synthesize and modify due to their small molecular weight and simple chemical structure, improving drug development efficiency.
  • They usually have good oral bioavailability, making treatment more convenient and improving patient compliance.

Challenges:

  • Small molecule drugs often have a short half-life, requiring frequent administration to maintain therapeutic effect.
  • They typically have high metabolic and excretion rates, limiting their duration of action in the body.
  • Their selectivity and specificity can be lower, leading to nonspecific interactions and side effects.

Despite these limitations, small molecule drugs remain the main direction in drug research and development, with broad application prospects in clinical use and the market.

The Significance of Developing Large Molecule Targets

Large molecule targets refer to proteins or other biological macromolecules with larger molecular weights. Their characteristics and application areas are of significant importance in drug development. Large molecule targets, usually having complex structures and functions, present a more complex and challenging drug development process compared to small molecule targets.

Firstly, large molecule targets have higher specificity. Due to their complex structure and function, large molecule targets usually have higher specificity and can interact more precisely with drugs. This gives large molecule targets better selectivity in disease treatment, reducing adverse effects on normal cells.

Secondly, large molecule targets have a broader range of applications in drug development. Large molecule targets play important roles in various disease fields, such as cancer, immune system diseases, and neurological disorders. Drug development targeting large molecule targets can achieve precise treatment of these diseases, improving treatment outcomes and patient quality of life.

Moreover, large molecule targets present certain challenges in clinical application. Due to the complexity and difficulty in preparing large molecule drugs, their clinical application often faces challenges. For example, the production cost of large molecule drugs is high, requiring more complex manufacturing processes and equipment. Additionally, the stability and pharmacokinetics of large molecule drugs in the body need further research and optimization.

Small Molecule Drugs Targeting Large Molecules

A recent article published in C&EN anticipated the prospects of small molecule drugs, suggesting a new phase in their development and significant role in the pharmaceutical field. New types of small molecule drugs, such as molecular glues and PROTACs, are continuously advancing to promote the treatment of human diseases. Additionally, the application of artificial intelligence is directly promoting the design and development of small-molecule drugs.

Currently under clinical research PROTACs drugs in China (Source: Essence Securities Research Center)

Currently, Kyinno Biotechnology is actively engaged in the research and development of small molecule drugs targeting a range of significant targets. Among these, CD33, CD30, HER2, CD22, CD79b, Nectin-4, BCMA, EGFR, CD19, Tissue Factor, and FRα are mature targets for marketed small molecule drugs. Kyinno Biotechnology is also focusing on under-research targets including HER2, EGFR, CLDN18.2, TROP2, c-Met, CD19, PSMA, Muc1, BCMA, and PDL1. This commitment underscores Kyinno Biotechnology’s dedication to advancing in the field of developing large molecule targets, leveraging the potential of small molecules in novel and innovative ways.

Many small molecules are being studied and developed in developing large molecule targets:

  • Anti-cancer drugs: Including small molecule inhibitors targeting protein kinases, such as Gefitinib and Erlotinib for the treatment of EGFR-positive non-small cell lung cancer; and small molecule inhibitors targeting proteases, such as Imatinib for the treatment of chronic myeloid leukemia.
  • Immune modulating drugs: Including small molecule inhibitors targeting immune checkpoints, such as Ipilimumab and Nivolumab for the treatment of malignant melanoma.
  • Inflammatory disease drugs: Including small molecule inhibitors targeting inflammatory mediators, such as Apabetalone for the treatment of cardiovascular diseases.
  • Antiviral drugs: Including small molecule inhibitors targeting the viral replication process, such as Oseltamivir for the treatment of influenza virus infection.
  • Neurological disease drugs: Including small molecule modulators targeting neurotransmitter receptors, such as dopamine receptor agonists for the treatment of Parkinson’s disease.

The development of covalent inhibitors, protein degradation technologies (such as PROTACs), molecular glues, molecular gates, and artificial intelligence offers more modes and methods for small molecule drug design and development, potentially accelerating the launch of new drugs and reducing development costs.

 

According to a report by Mordor Intelligence, the small molecule drug discovery market is expected to reach 52.35 billion USD in 2023 and grow at an annual rate of 8.76%, reaching 79.67 billion USD by 2028. Companies such as ICON Plc, Charles River Laboratories, and Labcorp play significant roles in this market. According to a report by X-MOL, in the 2022 drug sales performance Top 10, biologics occupied 6 spots, and small molecule drugs occupied 4 spots. However, considering the high production cost of biologics, small molecules may have a more impressive performance overall. According to an article published in Medicine in Drug Discovery, small molecules are still within the scope of innovative drug development. Approximately 90% of all drugs sold globally are small molecules. Their RNA targeting activity, anti-cancer activity, antiviral activity, etc., are being gradually discovered. Moreover, considering factors like cost, target audience, and new technology development, small molecules still occupy an irreplaceable position in the treatment field. Of the 293 new chemical entities (NCEs) approved by the FDA from 2017 to 2022, 182 were small molecules. Both in terms of quantity and actual market situation, small molecule drugs still dominate the pharmaceutical market.

Future Directions and Challenges

According to a report by Mordor Intelligence, the small molecule drug discovery market is expected to reach 52.35 billion USD in 2023 and grow at an annual rate of 8.76%, reaching 79.67 billion USD by 2028. Companies such as ICON Plc, Charles River Laboratories, and Labcorp play significant roles in this market. According to a report by X-MOL, in the 2022 drug sales performance Top 10, biologics occupied 6 spots, and small molecule drugs occupied 4 spots. However, considering the high production cost of biologics, small molecules may have a more impressive performance overall. According to an article published in Medicine in Drug Discovery, small molecules are still within the scope of innovative drug development. Approximately 90% of all drugs sold globally are small molecules. Their RNA targeting activity, anti-cancer activity, antiviral activity, etc., are being gradually discovered. Moreover, considering factors like cost, target audience, and new technology development, small molecules still occupy an irreplaceable position in the treatment field. In the 293 new chemical entities (NCEs) approved by the FDA from 2017 to 2022, 182 were small molecules. Both in terms of quantity and actual market situation, small molecule drugs still dominate the pharmaceutical market.


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Reference:

AstraZeneca. (2022, August). A big future for small molecules: targeting the undruggable.

Howes, L. (2023, October 30). Is this a golden age of small-molecule drug discovery? With innovative tools and techniques, it’s an exciting time for medicinal chemists building new drugs. C&EN, 101(36), 28-32. Retrieved from https://pubs.acs.org/doi/10.1021/cen-10136-cover

Lu, B., & Atala, A. (2016). Small Molecules. In In Situ Tissue Regeneration.

Dougherty, E. (2020, March 27). Visualizing molecular glues.

Makurvet, F. D., et al. (2021). Biologics vs. small molecules: Drug costs and patient access. Medicine in Drug Discovery, 9, 100075.

[Author Unknown]. (n.d.). ‘Small molecules are sexy again’: Gate Bioscience debuts with $560M and a new way to stop disease-causing proteins.


Kyinno Biotechnology, specializing in cancer drug development, operates globally with advanced cell line engineering and patented antibody discovery technologies. With extensive lab facilities and over 700 global partners, we are dedicated to being a long-term, reliable partner in the pharmaceutical industry, guided by its principles of Service, Focus, Quality, and Efficiency.