Screening Compounds Against the Hedgehog Pathway 3/2/05


James Chen, PhD, assistant professor, Stanford University, and his group are interested in the role of the Hedgehog (Hh) signaling pathway in cancer proliferation. The group is collaborating with ChemDiv Inc., San Diego, on the design and evaluation of compound libraries for Hh pathway screens.
The interest in Hh is from both a scientific and therapeutic standpoint. “We’re interested in the molecular mechanisms of development,” says Chen. “There is also a growing appreciation that developmental signaling pathways are involved in cancer later on if they are aberrantly activated in children or adults.”

The Hh pathway seems to be involved in many different types of cancers, including basal cell carcinoma, medulloblastoma, pancreatic cancer, small cell lung cancer, prostate cancer, and possibly breast cancer.

“The bottom line is that there are a lot of cancers now that seem to require Hh signaling for their proliferation or maintenance,” says Chen. “I think it’s consistent with a growing idea that stem cell populations are actually an integral part of oncogenesis and that the Hh signaling pathway is involved in stem cell maintenance.”

Molecules that affect the pathway can be useful as probes to illustrate how the pathway works biochemically, says Chen, and compounds that modulate the pathway are potential therapeutic leads, because of the role of Hh pathway in cancer and the potential for negative regulators of the pathway to be anticancer agents.

“Going from a hit to something that is useful as a biological probe or as a therapeutic lead involves a lot of medicinal chemistry, which is not easily done in an academic setting,” says Chen. “Our collaboration with ChemDiv is unique and could serve as a model.” The company will build compound libraries around the leads that come up and Chen’s group will re-screen these compounds in cell-based assays for the Hh pathway in their own high-throughput screening center at Stanford.

There are two known compounds that modulate the Hh pathway. One is called cyclopamine, a natural product that is inhibitory of the pathway. The other compound, called Sag, activates the pathway. Both drugs, Chen found, bind to a 7 trans-member protein within the pathway called Smoothened that is required for Hh signaling.

“These compounds that are teratogenic (cause birth defects), and are therefore things you would normally be quite afraid of, may actually have great therapeutic value in treating cancer,” says Chen. “They would be specific for this pathway, which is integral for the development of a fetus, but is, for the most part, not required in adults. So the hope is that the side effects would be much less than you would get with conventional chemotherapies that just target proliferating cells.”

Chemical Diversity has been working in collaboration with Chen on the design and evaluation of compound libraries for Hh pathway screens. Most of the compounds that have been found so far target Smoothened, which, Chen says, seems to be especially sensitive to small molecules, possibly because the ligand for Smoothened is actually a small molecule.

“In terms of oncogenic lesions, there are mutations in proteins like Patched, which is a negative regulated pathway and Smoothened, which make it active. Many of those mutations are resistant to cyclopamine, suggesting a relationship between them. There is also a direct association between cancer and the Hh protein.”

“With a compound like cyclopamine or other inhibitors of Smoothened you can go after things that are due to Hedgehog expression or loss of Patched function, but mutations in Smoothened are more resistant and things that would affect downstream components are then useless. The goal is to try to find compounds that affect this pathway, but in particular, one that acts more downstream than these current compounds do. The collaboration could lead to probes that are useful and potential leads that I don’t think we could do very easily on our own,” says Chen.

For ChemDiv the collaboration offers a way to expand into an area that is of interest to academia and big pharmaceuticals but one that would be considered too high-risk for a big pharmaceutical to investigate. “This project would be considered high-risk to a big pharma because you can not guarantee immediate payback in the common one-year term,” says Alex Kiselyov, PhD, VP of global chemistry. “This is our niche.”

By Elizabeth Tolchin
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