First targeted drug may end cancer-promoting Skp2's days of dodging bullets

A protein called Skp2, overexpressed in many types of cancer, for years has gotten away with promoting tumor growth and progression unhindered by effective treatments.

Hui-Kuan Lin, Ph.D., of Molecular and Cellular Oncology, has spent the last decade characterizing Skp2 and how it fuels cancer growth, and the past five years looking for a way to shut it down.

Lin teamed with Shuxing Zhang, M.D., Ph.D., in Experimental Therapeutics, to find an inhibitor that shuts down Skp2 among a galaxy of drug candidates. Their discovery, opening a completely new avenue for potential cancer treatment, was published today at the leading journal Cell.

The compound selectively attacked prostate, lung, liver and bone cancer cells in lab experiments while largely sparing normal cells. It also suppressed prostate cancer stem cells, which are thought to drive cancer progression and metastasis. In mouse models, the drug shrank tumors and overcame resistance to chemotherapy. "The beauty of this study is we identified an inhibitor and showed how it functions to block Skp2. Inhibitors often are discovered without an initial understanding of how they work," Lin said. Steps are under way to define the drug's potential off-target effects before it can advance to human clinical trials. In a series of major publications in recent years, Lin and colleagues have nailed down the details of the cancer-promoting effects of overactive Skp2:

• Destruction of a key protein in a process that renders cells senescent -- incapable of division.
• Activation of glycolysis, the processing of glucose into energy, the preferred diet of many cancer types.

To this deep biological understanding, Zhang and colleagues added expertise in chemical and structural analysis of proteins. Skp2's structure has been known for 10 years, making the protein a logical target for cancer therapy, Zhang said, but it presented two major obstacles. Targeting protein-protein interactions is already difficult and Skp2 has a huge area where it interfaces with other proteins, making it hard to find one small molecule to completely block that surface.

"To begin such a search, to rationally design a drug, you must first understand the target's biology and then look at its structure and fully comprehend its complex interactions and how disrupting those will help treat the disease," Zhang said. "Once you understand those, you're ready to screen using computer models."

That analysis is important. "There are many more chemical compounds available than there are estimated stars in the universe," Zhang said. "We have a database with 10 million compounds, but our prescreening analysis narrowed our computerized search to 120,000."

Virtual screening of the 120,000 compounds revealed 25 candidates that connect to either or both of two binding pockets on Skp2. Additional analyses showed that Compound #25, also known as SZL-P1-41, effectively disrupted Skp2's activity.

The inhibitor plugs critical binding sites on Skp2, preventing it from connecting to its cousin Skp1 to form a complex, the first step in its two cancer-promoting functions, Lin said.

Cell line experiments confirmed the compound's binding ability and revealed that the drug attacks cancer by reversing the effects discovered by Lin's lab: the senescence program is turned on, the cancer-feeding glycolysis pathway is turned off.

Zhang and Lin have filed a patent on this work.

Additional information Cell paper MD Anderson news release