Small molecule drug first to target circadian clock proteins to treat glioblastoma

By The Science Advisory Board staff writers

September 27, 2022 -- Keck School of Medicine researchers have demonstrated that circadian clock proteins, which help coordinate changes in the body’s daily functions, are also key to glioblastoma proliferation.

Their research, published September 26 in the journal Proceedings of the National Academy of Sciences, led them to identify SHP656 -- a small molecule that targets circadian clock proteins.

Glioblastoma patients typically undergo surgery, radiation, and chemotherapy, which shrinks most tumors substantially. However, in most patients the deadly cancer returns, now resistant to conventional treatment; survival rates are poor.

Researchers believe some cancer stem cells are left behind following treatment. These stem cells hijack the body's circadian clock machinery, enabling their rapid spread. The researchers created and tested thousands of molecules capable of binding to -- and potentially neutralizing -- the "rogue" circadian clock proteins inside cancer stem cells.

Artificial intelligence algorithms modeled how each new molecule would bind to these proteins. SHP656 had the best "lock-and-key" fit.

When tested against glioblastoma stem cells, SHP656 reduced cancer stem cell growth but did not harm normal stem cells. In Synchronicity Pharma's phase I clinical trials, SHP656 appears safe in healthy volunteers. Phase II trials in glioblastoma patients may begin in a few years.

"This is a potent molecule that's very exciting to us in terms of its potential for deployment against glioblastoma," said senior author Steve Kay, PhD., Keck School of Medicine professor and co-founder of Synchronicity Pharma. "We're now starting to march down the path of clinical drug development -- turning this from a science story into a translational one."

Disclosure: Steve Kay serves on the board of Synchronicity Pharma and receives financial compensation for his role.

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