Small Molecules

Small molecules are everywhere. The chemistry community readily uses the term "small molecule" to describe a biologically active compound that is not a protein or a polymer. Chemists are now dedicating their careers to explore the process of using these little guys to solve important biological questions. The New York Academy of Science hosted a seminar recently titled "Accelerating Drug Development with Innovative Discovery Platforms." Representatives from the biotech industry and academia attended. They described innovative research and highlighted small molecule compounds that have been developed into drugs successfully.

The day was started by David J.Bearss, Ph.D. Vice President and Chief Scientist at SuperGen Inc. He suggested that the high cost of drug development in today's market (800 million – 1.2 billion per drug!) is creating a new mood of minimalism in the pharmaceutical community. The big drug companies are scaling back their research efforts and are relying more on smaller companies to develop drug candidates for clinical trials. To fill this niche, SuperGen has developed a new computer algorithm called CLIMB that identifies small molecules that should bind a specified molecular target.

The field of chemical biology has historically relied on high throughput screening to identify drug candidates. In essence, the chemists pours thousands and thousands of chemical molecules, found in a chemical library, over a protein of interest and visualizes the reaction between the compounds. In reality this is a very complex process that relies heavily on the type of chemical library available to the scientist. A good library is made up of small molecules that encompass many different types of chemistry modalities. Yet often times, the best libraries are difficult or too expensive to obtain. Once a type of chemical is established to have reactivity with the chosen target, that chemical type is optimized and similar or "like" compounds are tested for better binding of the selected protein or target. SuperGen Inc. hopes to predict which chemical type will be selected in the first round of screening based on structural data of the molecular target. Their computer program models successful compound interactions and assists the executive in making go/no go decisions regarding further funding of a drug candidate. Thus far, SuperGen Inc. has successfully predicted a PIM kinase inhibitor that causes tumor regression in acute myologenous leukemia (AML) xenograft models (a xenograft model: human tumor tissue or cells are transplanted into mice or rats followed by tumor treatment regimens).

SuperGen's CLIMB technology aims to improve the accepted dogma in small molecule drug development by making the process more efficient. The second speaker, Randal Peterson, Ph.D., assistant professor of medicine at Harvard Medical School, decided to change the process altogether (Fig. 1 below). Dr. Peterson's group injects small molecules into Zebrafish and looks for phenotypes of interest and only then identifies the molecular target involved. Zebrafish are an ideal model organism because they allow for efficient whole organism screening. They are small enough to fit into wells and are conducive to systematic drug treatment. One example of this new process involved Bone Morphogenetic Proteins (BMPs), which have been shown to be implicated in carcinoma and anemia of chronic diseases. BMP's are also involved in various developmental processes in vertebrates. In Zebrafish, BMP are integral to the proper formation of the dorsoventral axis. Genetic studies have shown that antagonism of BMP causes ventralization, increased ventral development at the expense of dorsal structures and inhibition of BMP dorsalizes the Zebrafish organism. Therefore, Dr. Peterson's lab looked for small molecules that dorsalize zebrafish and identified a compound called dorsomorphin (Image 1 below). The compound is now being optimized for further study.

Standard Process for Chemical Screen:

Target --> Modifier (small molecule) -->Phenotype

Process Used by Dr. Peterson:

Phenotype --> Modifier (small molecule) --> Target

Image 1: dorsomorphin

The day finished up with a panel discussion and questions from the audience. The moderator asked the first question: "Is there a clinical trial bottle neck?" The seminar explored all the effort and time spent developing drug candidates in a more efficient and successful manner. The community is now revolutionizing the process of drug development. The goal is to cure disease and treat patients. If these compounds cannot be properly tested through phase III clinical trials, the whole process of drug development becomes moot. The speakers addressed this issue but focused on drug development and the need to have compounds fail earlier in the pipeline. If the drug development process is improved more successful candidates will be tested and hopefully clinical trials will be improved. Everyone agreed, however, that clinical trials are already limited in scope and could someday be the bottleneck of drug development.

Something relevant: An article came out this week in the New York Times discussing the outsourcing of clinical trials.

Something interesting: Pentacosane, a linear small molecule made up of a strand of 25 carbons held together by single covalent bonds, is released by female ants when they are fertile. It was recently shown by a group at Arizona State University that if a queen ant is present, any ants releasing this compound are ostracized and physicaly intimidated by the other worker ants. If there is no monarch, the fertile ladies are left alone.

Something crazy: The American Museum of Natural History in New York is now awarding PhDs in comparative biology!

A joke at every end:

How many graduate students does it take to screw in a light bulb?
Only one, but it may take up to five years for him to get it done.