A Few Q&As about Small Molecule Inhibitors

In recent years, many new therapy approaches has emerged in the field of cancer treatment. The monoclonal antibody drugs approved each year is on the rise, and the immunotherapy represented by anti-PD-1/PD-L1 antibody is rewriting the pattern of cancer treatment. In addition, cell therapy, represented by CAR-T therapy, is officially on the stage, bringing a totally different treatment to blood cancer. Facing these endless stream of advanced therapies, traditional small molecule therapy seems to have lost its glory of the past. Under such circumstances, one cannot help but think that if small molecule drugs are now outdated.

The truth is that small molecule drugs are still valuable, and have great research and development potentials with the aid of advanced research tools. For example, structural biology tools have been significantly improved, so we can get more information from potential compounds and their biological targets. In addition, automation and artificial intelligence can help make new drug discovery faster and more accurate. The following are several most heated questions concerning small molecule inhibitors.

1. What are the advantages of small molecule inhibitors compared to biologics, cell therapy, and gene therapy?

When it comes to the advantages of small molecule drugs, many people immediately think that it is less complex than biological drugs in CMC, namely chemical, manufacturing and control.

Because of the cost of raw materials, small molecules are cheaper and also easier to manufacture. The cost of synthesizing small molecules may be a fraction of the cost of producing antibodies or proteins. Not only are they easier to manufacture by synthetic methods, but the analysis of the properties of the compounds is also straightforward because there are no problems with post-translational modification heterogeneity or conformational differences. The development of small molecule drugs does not necessitate some of the analysis required to develop biological agents.

Another important advantage of small molecules is that they can be conveniently administered orally, especially for treating chronic diseases; however, antibodies and proteins must be administered intravenously. Small molecule drugs can be made into tablets as long as they have suitable properties. Although different methods of delivery of proteins and antibody drugs have been studied, biological agents rarely have the potential for oral administration.

In addition, small molecules can be combined with intracellular targets. Therefore, they have become the drug of choice for targeting intracellular targets because it is difficult to deliver proteins to other parts of the cell, except for endosomes and lysosomes. Of course, gene therapy or RNA therapy may deliver proteins to most cell compartments, but small molecules are the best choice for binding to intracellular targets.

1. Are small molecule drugs advantageous to any specific diseases?

In general, if the target binds to small molecules and we can find these small molecules, small molecules are a better choice because they are easier and less costly to manufacture.

Biologics are generally suitable for situations where small molecule therapy is not available for some reason. For example, many companies are committed to antibody therapy; meanwhile, cancer research is now mainly focused on anti-PD-1, PD-L1 and CTLA-4 antibodies as a result of the increasing status of immunotherapy. Only antibodies can address target specificity or cell type specificity.

It is worth noting that for genetic diseases that may be cured by single-dose gene therapy, gene therapy is preferable, compared to taking small molecules or protein drugs since they can only regulate certain functions, while gene therapy may cure hereditary diseases.

Small molecule drugs will certainly not disappear, but cell therapies, gene therapies and antibodies are indeed currently gaining a lot of attention in the biopharmaceutical industry.

1. Can small molecule drugs be used to improve our understanding of biology?

Biology is very complex, and a very good way to unravel the mysteries of biology is to have a good specific small molecule to study the target. For example, MEK and BRAF inhibitors play a pivotal role in understanding their signaling pathways and their role in cancer.

For years, many researchers have used genetic knockouts and other models for biological research on the Hippo-YAP signaling pathway. However, it is believed that a series of compounds could be used to inhibit YAP activation, which would provide us with unique insights into the Hippo-YAP signaling pathway. By using these small molecule compounds as chemical tools, researchers are able to better understand the role of this signaling pathway in certain cancers and know how to regulate this pathway to treat these cancers.

1. Is combined therapy promising in the future? How will it evolve in the next five to ten years?

Currently, small molecule drugs, biological agents, cell therapy and gene therapy are the most popular treatment modes. People have tried many combination therapies in oncology, but some of these combinations are not very reasonable at all. In the future, such combination of drugs should be based more on rational design, action mechanisms and complex assumptions.

Biology is very complex, and in the next decade, the experimental process will still dominate the development of all classes of drugs, which means that the experiment itself will not be replaced by machine learning or computing tools. Future combination therapies may include more gene therapy, oligonucleotides, and cell therapies, while in the past research is more focused on small molecules, antibodies, and therapeutic proteins.

The reason why the new therapeutic models of gene therapy, cell therapy, and oligonucleotides will increase in the future combination therapy is that they are still rare. The success of these new treatment model studies in the future will increase their percentage in combination therapy. In some areas, they can better address unmet medical needs than proteins, antibodies or small molecules. Therefore, we will see more of them in combinations and will see all these treatment models continue to grow and mature.