Editorial Article

Small Molecule Drugs Development: Where to Go?

Yuyong Ma
Chemistry and Biochemistry Department, University of California, San Diego- United states
*Corresponding author:

Yuyong Ma, Chemistry and Biochemistry Department, University of California, San Diego- United states, Email: thomsonma86@yahoo.com

In recent years, the drug discovery success has been driven mainly by biologics, which currently represent a sizable portion of the top-selling drugs. Nevertheless, the advantages including oral availability, relatively easy to make, scalability, and low cost make small molecule drugs still indispensable for human health and well-being, which still account for about 90% of the therapeutics in today’s pharmaceutical market. Although facing the challenges from biologics, the development of small molecule drugs is still promising with the constant innovation of technology.

The success of the penicillin and many other antibiotics marked the tremendous success of the modern pharmaceutical industry which has changed the world in many ways. 1 In the early days of drug discovery, small molecules were dominant without any competitors. However, since the first biologic drug, recombinant human insulin (Humulin® R), was approved by FDA in 1982, the biologic drugs have made amazing progress in drug discovery. The targets of biologics are usually specific cell receptors associated with the disease process. For example, they can bind to the receptors of cancer cells selectively, making it possible to alter the function of or kill specific abnormal cells while the healthy cells are intact in this process. The high target specificity of biologics leads to many advantages over small molecule drugs including minimal safety/toxicity issues and well-understood mechanisms of action. The biologics achieve great success and the market share increases dramatically in recent years. According to Evaluatepharma, the global market share of biologic drugs is 23% in 2014 while the number is only 14% in 2006. It is expected that the number will increase to 27% in 2020.2 Despite the enormous success of biologics, the high price and administration by injection of most biologics make the small molecules remain prevalent in both development pipelines and on the market.

Small molecules are usually administrated orally and the released active substance can be absorbed into the bloodstream via the intestinal wall. This is a great advantage, especially for long-term use in the treatment of chronic diseases. The small molecules can also penetrate cell membranes and reach almost any desired destination through the circulatory system in the body because of their small size and adjustable hydrophilic properties. Small molecule drugs are simple, well defined and independent of the manufacturing process. In addition, they are also easy to make by chemical synthesis and scalable which make the cost of manufacturing very low. These advantages have driven the investigators to discover truly innovative small molecule drugs. To explore the full potential of small molecule drugs, there is still a lot of work to do.

1. Development of new therapeutic strategies and synthetic methods to explore new chemical space. The enormous progress of chemical synthesis, providing millions of small molecules for screening, contribute a lot to the success of the development of small molecule drugs in the last several decades.3-4 The largest pharmaceutical companies typically contain approximately 106 compounds. Once a new target is identified, researchers would screen millions of compounds in the search for the biologically active molecules. These compounds are called hits and will be used as a starting point for the medicinal chemistry. Obviously, a larger compounds library stands a bigger chance to win in drug development.5-6 Although chemical space is practically infinite, the availability is limited by the chemical synthesis and our knowledge about the biological systems and their molecular diversity. Until today, medicinal chemists only explore a very small fraction of the chemical space. Once a new therapeutic strategy was developed, the new area of chemical space will be explored. A case in point is the recently developed siRNA drugs.7 With the development of molecular biology and gene therapy, RNA interference (RNAi) was found to be a powerful endogenous and specific gene silencing drug for human therapy. The new concept and technology attract a great effort to harness the tool to fight against various diseases. RNAi uses small interfering RNA (siRNA), known as short interfering RNA or silencing RNA to suppress the expression of genes with complementary sequences, resulting in no translation. The siRNA is 20-25 base pairs in length, similar to miRNA, and operates within the RNA interference pathway. The clinical studies have already begun to test the therapeutic potential of small RNA drugs that silence disease-related genes by RNAi. Recently, it was found that Ebola-targeted siRNAs was effective in the non-human primate with 100% survival rate from a lethal dose of Zaire Ebolavirus, which make the siRNAs a promising post-exposure prophylaxis in humans.8 To enhance the therapeutic properties, such as enhanced activity, increased serum stability, fewer off-targets and decreased immunological activation, medicinal chemists also chemically modified the structures of siRNAs.

Besides, current organic synthetic methods usually produce the molecules with the atoms dominantly connected by C (sp2)-C (sp2) bonds. In contrast, many natural product-derived drugs are much more complex, such as Taxol and Erythromycin. The emergence of new therapeutic strategies and synthetic methods will lead us to explore the untouched area of the chemical space to discover more small molecule drugs.

2. The innovation of computational chemistry models to facility the drug development. According to the Tufts Center for the Study of Drug Development (CSDD), the out-of-pocket cost of bringing a drug to market is about $1.4 billion in 10-plus years. To reduce the cost of drug development is the most challenging topic today. A possible solution to this is turning to the computer for help.9 Chemists used to understand the structures of substances with models using plastic balls and sticks. The award of 2013 Nobel prize in chemistry to Martin Karplus, Michael Levitt and Arieh Warshel marked the importance of computational chemistry in understanding and predicting chemical processes. In the last several decades, the steady pace of incremental improvements has increased the computation’s role in the field but far more less than expected. Today’s computational chemistry has gained success in protein structure determination, but a lot of still need to be done on the fragment-based discovery, cheminformatics, phenotypic screening and the design of protein therapeutics. The computational chemistry is usually used to explain an observed phenomenon, but it is very hard to give a precise or good predictive results. On the one hand, the biological processes are too complex to degenerate into a simple model, and on the other hand, the computational ability is limited by current technology. It is no doubt that the breakthroughs in the computer-based simulation of biochemical processes and the molecular model building will play a critical role in drug design. Once the ever cumbersome and costly experiments including assays and animal tests could be carried out on computers, the efficiency will be improved and the productivity will be enhanced greatly. Actually, the largest pharmaceutical companies have already envisioned the potential of computational medicinal chemistry and begin to apply computational chemistry and cheminformatics to process development, analytical chemistry, and biologics. This future has already begun.

3. Targeted drug delivery to reduce off-targets and toxicity. In traditional drug delivery systems, the drug is distributed throughout the body and only a small portion reaches the organ to be affected, such as in chemotherapy where roughly 99% of the drugs administered do not reach the tumor site. To overcome the problems, the targeted drug delivery is devised to improve efficacy while reducing side-effects. Targeted drug delivery seeks to enhance the distribution of the drugs in the intended sites while reducing the concentration of the drugs in other tissues. In this way, the therapeutic effects of the administrated drugs would be fully explored.  One strategy is to use vehicles including polymeric micelles, liposomes, lipoprotein-based drug carriers, nano-particle drug carriers, and dendrimers to deliver the drugs to the tissues or cells of interest.10 The other strategy is the conjugation of the small molecule drugs to a monoclonal antibody (mAb) to make full use of the highly potent small molecule drugs and the highly selective mAbs. The complex is called antibody-drug conjugate (ADC) which provides the possibility to selectively cure various diseases.11 The success of the ADC is marked by the approval of Adcetris (Seattle Genetics) and Kadcyla (Roche) by FDA. According to the Research & Markets, the sales of ADC will increase to $ 10 billion in 2024. The targeted drug delivery will enable many failed drugs to find their new positions in the drug market. 

4. Development of precision medicine. The concept of precision medicine is making specific treatment and prevention protocols based on both of the genetic and nongenetic differences of individulas.12 Precision medicine will allow doctors and researchers to perform treatment and prevention strategies on different groups of people for a particular disease. Developments in genomics, proteomics, and molecular pathology have generated many candidate biomarkers with potential clinical value.13 The diagnosis results will be greatly improved with these biomarkers, leading to a more specific treatment. The philosophy of precision medicine has been employed to save the failed drugs due to lack of efficacy or undesirable adverse effects. 

It is well known that clinical trials are extraordinarily expensive and each year many drugs, unfortunately, fail after phase III studies have been completed, largely due to lack of efficacy or undesirable side effects. Denovo Biopharma devised a technology to identify novel genetic biomarkers by scanning the entire human genome. The collected data will then be analyzed and used to help the drug developers to design new clinical trials in smaller and targeted patient population with much lower cost and higher success rate.  With this technology, they purchased Enzastaurin failed after phase III studies from Lily and developed it into a personalized anticancer drug which is currently under phase IIb clinical trial.  The development of precision medicine in the pharmaceutical industry will no doubt make more small molecule drugs available in markets.

Although facing the competition from the biologics, the small molecule drugs, are still dominant and vital in many areas. The great success of the Sovaldi, a first-in-class therapy for hepatitis C marks the pharmaceutic power of small molecule drugs at present. With the advancement of the new technologies and strategies, the small molecules will remain prevalent in both development pipelines and on the market in the expected future.

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Published: 14 April 2017


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