Open-Source Approach May Speed Drug Discovery

In an effort to speed early-stage drug discovery, a Toronto, Canada–based research group has developed and made freely available an early-stage compound that shows promise in targeting a protein involved in breast cancer and leukemia.

Scientists at the Ontario Institute for Cancer Research (OICR) and the Structural Genomic Consortium (SGC) in Canada jointly developed a compound called OICR-9429, which inhibits WD-Repeat Domain 5 (WDR5), a protein involved in cell-cycle progression, apoptosis, gene regulation, and other cellular processes.

“Our goal is to identify proteins that are the most druggable and make inhibitors to them easily available to researchers in order to probe the biology faster than we could do on our own,” says Rima Al-awar, PhD, director and senior principal investigator of OICR's drug discovery program. “That way we can identify the best targets and decide which disease areas to focus on.”

Since the compound was first made available in May 2014, two separate research groups have initiated investigations and published their findings.

In one study, published in Nature, researchers at the University of Pennsylvania in Philadelphia used OICR-9429 to halt tumor cell growth in a panel of breast cancer cell lines with p53 mutations, which are present in many cancers. The researchers knew from past studies that p53-mutated tumors are associated with upregulation of methyltransferase MLL1, and that it is possible to inhibit MLL1 function by targeting its interaction with WDR5. They demonstrated that the mutant p53 protein binds to and upregulates components of a histone methyltransferase complex that promote tumor-cell growth by interacting with WDR5. OICR-9429 seemed to inhibit that interaction.

In a second study, investigators at the CeMM Research Center for Molecular Medicine in Vienna, Austria, showed that the mutant protein p30, the most common CEBPA mutation in acute myelogenous leukemia (AML), preferentially interacts with WDR5, a key component of SET-domain/mixed-lineage leukemia histone-methyltransferase complexes. By inhibiting WDR5, OICR-9429 effectively stops cell growth in p30-expressing human AML cells with CEBPA mutations. The findings were published last month in Nature Chemical Biology.

Using an open-source approach allows OICR and SGC to collaborate with multiple teams of researchers simultaneously and facilitate sharing of results, says Al-awar. Eventually, the organizations want to partner with drug companies to develop promising drug candidates.

“Both of these studies provide a scientific rationale as to why inhibiting WDR5 activity would reverse certain oncogenic drivers,” says Cheryl Arrowsmith, PhD, chief scientist at SGC. “They demonstrate that OICR-9429 is a potent and selective antagonist of WDR5 with tumor cell–specific growth inhibition, and not generally toxic to cells.”

Several groups, including drug companies, have expressed interest in OICR-9429—which is available through SGC and several commercial distributors—and potentially partnering with OICR on further development, according to Al-awar.

“These publications show that the WDR5 protein is relevant and could have implications in disease,” says Al-awar. “Our hope is that further investigations made possible by the wide availability of OICR-9429 will clarify just how relevant WDR5 is as a therapeutic target.”