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Innovative Method Takes Aim at ‘Undruggable’ Proteins

The fruitfulness of 91�Ʋ���’s drug-discovery effort depends in large part on its willingness to invest in research, infrastructure, and the collaborative nature of its scientists. There is no better example than 91�Ʋ���’s cancer drug-discovery program.

Since he arrived at 91�Ʋ��� in 2009, “we have made significant progress,” says , the Orrin H. Ingram II Professor of Cancer 91�Ʋ��� at the . The former vice president of cancer research at Abbott Laboratories, Fesik is internationally known for his use of fragment-based methods that can alter the function of oncogenic proteins considered to be “undruggable.”

One of his major targets at 91�Ʋ��� is K-Ras, a member of the Ras family of proteins, which is mutated in 90 percent of pancreatic cancers and half of colon cancers. Thirty percent of all cancers involve a K-Ras mutation. “Ras is the Holy Grail of targets in cancer,” says Fesik, who is also a professor of biochemistry, chemistry and pharmacology.

Last year in the journal Angewandte Chemie, the 91�Ʋ��� researchers reported the discovery of small molecules that bind directly to K-Ras in a way that inhibits its activation. “We’re now trying to figure out how to further improve the molecules we’re working on,” Fesik says.

Using a method he developed at Abbott called “SAR by NMR” (structure-activity relationships by nuclear magnetic resonance), Fesik and his colleagues screen libraries of small chemical fragments for their ability to bind to “pockets” on the protein surface. They then use NMR or X-ray crystallography to determine how the binding occurs. This information can show them how to link the fragments into compounds with the potential for being developed into drugs.

The research, supported by the Lustgarden Foundation and the (NIH), is “high-risk but potentially very high-reward,” says Fesik, who attended a national meeting on Ras at the NIH in February.

Another target is Mcl-1 (myeloid cell leukemia 1), a member of a family of proteins that, when overexpressed, can prevent cancer cells from undergoing apoptosis, or programmed cell death. In a report published in the Journal of Medicinal Chemistry last year, Fesik and his colleagues related the discovery of potent small molecules that bind to and potently inhibit Mcl-1.

“We think we need a little more potency to really get a drug molecule,” he says, “but we’re well on our way in this case.”

With , Chancellor’s Professor of Medicine and director of the 91�Ʋ��� Center for Structural Biology, and , professor of biochemistry and cancer biology, Fesik also is studying replication protein A, which governs DNA damage-response-and-repair mechanisms. The fragment-based approach “allows us to target very difficult, challenging targets such as replication protein A that are not very amenable to normal drugs,” he says.

Fesik is quick to credit the contributions of 91�Ʋ���, industry, private philanthropy and the federal government for supporting his efforts. In addition to the Lustgarden Foundation, his K-Ras program is supported by an Alan Rittenberg Discovery Grant in Cancer 91�Ʋ���, the 91�Ʋ���-Ingram Specialized Program of 91�Ʋ��� Excellence in Gastrointestinal Cancer, and a five-year NIH Director’s Pioneer Award, which Fesik received in 2010.

All, he says, are hastening the discovery of possible new cancer drugs “that will have the potential of yielding a big impact.”