UCSF Magazine
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UCSF Magazine

Identifying potential new drugs is like trying to hit a target hidden inside a massively complex, constantly moving machine — with a single tiny arrow.

OUR SOLUTION: Explore molecular targets in daring new ways.

Illustration: Brian Stauffer

How can we keep the inner workings of our cells in check?

Inside each of our trillions of cells, thousands of proteins are busy maintaining a stable environment — doing everything from metabolizing nutrients to repairing genetic damage. To convey signals or carry out chemical reactions, these cellular proteins change shape, folding into new configurations that activate other proteins to each do their specific jobs. But sometimes an important protein gets bent into the wrong shape, leading to a cascade of harmful protein-protein interactions — a process that can lead to disease.

Michelle Arkin, PhD, co-director of the Small Molecule Discovery Center, has spent two decades uncovering details of this molecular interplay. By testing millions of molecules — with a particular eye for their influence on protein-protein interactions in test tubes — Arkin seeks to identify promising new drug candidates. She’s currently hot on the trail of P97, a protein that’s central to interactions which, if they go awry, can cause a variety of conditions, from neurodegenerative diseases to cancers. Illuminating P97’s role may lead to new therapies for those conditions.

Photos: Elisabeth Fall (left, middle); Alexa Rocourt (right)

How can we make drugs side-effect free?

Drugs that treat psychiatric diseases work by influencing neurotransmitter receptors. These are brain proteins — typically found in the spaces, or synapses, between nerve cells — that convey signals from one nerve cell to another. Many psychiatric drugs affect several types of these receptors, meaning they can cause not only the desired therapeutic effects, such as the alleviation of anxiety, but also undesired side effects, such as insomnia.

Brian Shoichet, PhD ’91, is using 3-D models of individual neurotransmitter receptors to design drug-like molecules that fit only into specific receptors — with the aim of alleviating side effects. He and his team recently discovered a highly selective molecule that activates a dopamine receptor subtype called D4. This finding holds promise for the development of medications to treat addiction and psychosis that don’t induce the movement disorders commonly associated with many of today’s psychiatric drugs.

Can a new point of view turn a drug discovery failure into success?

Decades ago, scientists noticed that cancer cells produce signals that promote tumor growth. They tried blocking some of those signals with a class of drugs known as PI3K inhibitors. The result? Tumors stopped growing — but only in petri dishes and animal models. In clinical trials, the drugs totally failed to extend the lifespans of cancer patients — so PI3K inhibitors were shelved.

Sourav Bandyopadhyay, PhD, wondered how such promising drugs could have stumbled at the finish line. Using a new technology that he developed, he measured the levels of all the different signals present in tumor cells and found that a handful of signals changed in response to PI3K inhibitors, allowing cancer to compensate for the effects of the drugs. Combining PI3K inhibitors with other drugs that block these additional signals led to an even more dramatic decrease in tumor growth in animal models, compared to PI3K inhibitors on their own. He’s now exploring ways to test this new combination therapy in clinical trials, making good on the therapeutic promise of one of cancer biology’s earliest discoveries.



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