Q&A with the Small Molecule Team
Andy Shiau and Tim Gahman came to Ludwig to help our scientists perform cutting-edge research and take their ideas from concept to clinical testing.
Three years ago, biochemist Andy Shiau (program director) and chemist Tim Gahman (director of medicinal chemistry) came to Ludwig to help our scientists perform cutting-edge research and take their ideas from concept to clinical testing. We recently had a chance to sit down with our San Diego-based ‘drug hunters’ and learn more about their unique group.
What are small molecules?
Small molecules are chemical compounds. They can be substances you find in nature or things chemists make in the lab. Table sugar is a small molecule. Vitamin C is a small molecule. So are drugs, including pain relievers like aspirin and antibiotics such as penicillin. Right now, small molecules make up about 90 percent of the drug market.
Why was the Small Molecule Discovery Program started?
Targeted small molecule therapies hold great promise for the battle against cancer. They block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression. In fact, today there are several small molecules that are targeted cancer therapies, for example Gleevec, which is approved to treat gastrointestinal stromal tumor, a rare cancer of the gastrointestinal tract.
The small molecule lab provides the Ludwig community around the world access to small molecule tools for research and helps them move basic scientific findings from the lab to a clinical setting.
How do you go about creating a small molecule?
Making any kind of drug is a technically exacting process. And making small molecule drugs is no exception. Once we’ve identified a target, we create molecules from scratch by using sophisticated computer modeling. At other times we apply a process called high-throughput screening, which can be used to quickly conduct millions of chemical tests on cells or proteins. Both of these approaches help us to determine what type of molecule controls the activity of a specific protein that tells cancer cells to grow and multiply out of control. We’re looking to slow or block these types of biochemical signals and cause cancer cells, but not normal ones, to die.
The results of these experiments provide starting points for understanding the interaction or role of a particular biochemical process in biology, an important early step in drug development. The chemical hits we get from our initial screening or design process are then optimized, or altered to make them more effective and safer. For example, we can modify a compound to make it less likely to interact with certain pathways in the body and reduce the potential for side effects, such as toxicity to a healthy organ.
We test hundreds or even thousands of compounds against a target to identify any that might be promising. And based on the results, we might select several lead compounds for further study. We’ve used these types of approaches to identify inhibitors of many proteins, such as enzymes and receptors that Ludwig scientists are interested in.
Can you give us an example?
We are working with Karen Oegema’s and Arshad Desai’s labs to use our polo-like kinase 4 (PLK4) inhibitors to figure out how normal and cancer cells divide. This is a pretty basic concept that we still have a lot to learn about. PLK4 is an important cell cycle regulator that’s involved in the regulation of centrosome duplication. Centrosomes help regulate the cell’s progression through the cell cycle. Errors in the centrosome duplication cycle may be an important cause of aneuploidy, a chromosome problem caused by an extra or missing chromosome, which may contribute to cancer formation.
We’ve screened multiple small molecules against PLK4 and identified one that potently and specifically inhibits the enzyme in both biochemical and cellular assays. If we find differences between the dependence of normal and cancer cells on PLK4 and centrosomes, we can use this information to make a totally new class of drugs targeting tumors in which PLK4 regulation is disrupted. Small molecules that target PLK4 could hold great promise as anticancer drugs.
What excites you about your work?
The incredible wealth of knowledge that has been generated with the sequencing of the human genome has really revolutionized the discovery and development of small molecule cancer drugs over the last decade. We’re moving from a one-size-fits-all approach that emphasized chemotherapy to a personalized medicine strategy that focuses on the discovery and development of molecularly targeted drugs that exploit the vulnerabilities of cancer cells. Because of its vision and resources, Ludwig is uniquely positioned to help in this transition. Why is it important that Ludwig undertakes drug discovery research?
Biological systems are very complicated, so it’s virtually impossible to foresee what projects will ultimately pay off. This makes it very expensive and risky. Many people think discovering and making drugs is like manufacturing cars or electronics. It’s a lot less predictable than that. Maybe one out of a thousand or even ten thousand projects will lead to a drug. So, the drug industry is more like Hollywood—it’s very hit driven. Pharmaceutical companies are reluctant to undertake early-stage research, and it’s getting harder to fund biotech startups as venture capitalists realize how much work and time goes into developing a drug. That’s why Ludwig is important. It’s willing to invest in research today to develop the drugs of tomorrow.
What is the biggest challenge the group faces?
Our biggest challenge is that we’re starting at the very beginning of the drug discovery process. We’re talking to people about ideas. We’re talking about results of an experiment that researchers have seen for the very first time. But we’re in the ideal place to take this approach because we have great colleagues who do fantastic science, the support of Ludwig, and a mission to deliver therapeutics. What gets you up in the morning?
Finding a small molecule drug that will drive cancer cells to suicide. Walking the halls and interacting with some of the world’s leading scientists. Working in an environment where people are constantly looking for answers and challenging themselves to do incredibly novel things.
Kick-starting the body’s own tumor-destroying systems to trigger cell death in cancerous but not healthy tissue is a project we’re working on with Benoît Van den Eynde. Understanding cholesterol metabolism in brain tumors and uncovering new biology are part of an exciting collaboration with Paul Mischel.
Bottom line: Driving the science forward gets us up in the morning.
And figuring out how to do that keeps us awake at night.