Researchers discover compound that can reverse cancer-causing mutation

Nir London progress 
By David Schiff

One of the biggest hopes for curing cancer is to develop treatments that target the genetic make-up of a patient’s specific tumor. To this end, Dr. Nir London, Phd. and his team at the Weizmann Institute of Science, Rehovot, Israel are focusing on the p53 gene, which has been described as “the guardian of the genome” because it prevents cancer formation. Funded in part by a grant from the Israel Cancer Research Fund, Dr. London’s team is developing compounds that can reverse genetic mutations that prevent p53 from doing its job.

In conventional drug research, once scientists discover a target molecule that controls an important step in a disease process, pharmaceutical companies screen huge libraries of small molecules looking for candidates that can bind to the target—to either stimulate it or inhibit it without disturbing other functions in the body. Recently computer models have taken a lot of the guesswork out of finding compounds that dock with target molecules.

Dr. London’s team has been looking specifically for compounds that are covalent—meaning that they form chemical bonds by sharing electrons between atoms. Until recently scientists could not predict which compounds would form a covalent bond—one of the strongest chemical bonds that exit.

“The ordinary binding of a small molecule to its target site can be thought of like fitting two puzzle pieces together,” Dr. London said. “Now think about gluing them together as well—that is the strength of a covalent bond. It is virtually unbreakable and with the right chemistry, irreversible.”

A problem with covalent compounds is that they tend to be promiscuous—they can bind to many targets, not just the one selected as the target for a potential drug.  So the challenge of finding a compound that will reverse mutation so that p53 can fulfill its cancer-prevention mission was accompanied by the even greater challenge of finding one that would not target healthy tissue. The strong, potentially unbreakable nature of a covalent bond made this especially crucial.

The team is using a set of programs that Dr. London developed that can evaluate the precise structural fit for new compounds that would form covalent bonds that are target-specific, not promiscuous. In the first 18 months of their research, the research team discovered the first series of compounds that is able to directly bind potently and selectively to the mutant p53 gene.

“This breakthrough exceeds our expectations”, Dr. London said. “We were able to determine structures of mutant p53 in complex with our compounds and further optimize them. We are currently using these structures to guide the design of this compound series to be able to re-active p53 in cells, thus turning on the cells’ intrinsic defense mechanism against cancer. In the second half of this project we will develop the covalent compounds as starting points for personalized cancer therapeutics and diagnostics, with the potential to impact the lives of hundreds of thousand of patients each year who have this specific mutation.”

Categorised in: ICRF Blog