New research led by scientists at Mount Sinai, New York, has used a structure-based designing approach to develop a small-molecule chimera called MS67 that targets protein degradation mechanisms and specifically breaks down WDR5—a propeller-shaped protein that contributes to tumorigenesis of a wide range of human cancers including both solid tumors and blood cancers.

The study establishes the superiority of pharmacological degradation of WDR5 as a promising therapeutic strategy for treating WDR5-dependent tumors over earlier strategies that employed WDR5 inhibitors.

WDR5 (WD40 repeat domain protein 5) binds to chromatin-modifying complexes at the proto-oncogene called MLL (for mixed-lineage leukemia) that is mutated in a variety of human leukemias. This drives the proliferation of a type of acute myeloid leukemia (AML) that is more commonly found in children and responds poorly to standard treatments. Current inhibitors that keep WDR5 from binding to its downstream targets have not been effective in curbing cancer in animal model studies.

Using a battery of biochemical, biophysical, structural, cellular, genomic, in vitro, and in vivo studies, the researchers in this study show MS67 is effective in suppressing this type of acute myeloid leukemia and is a much superior therapeutic agent than other therapies that inhibit instead of degrade WDR5.

The authors compare the new WDR5 degrader to those developed earlier, in a patient-derived mouse model of acute myeloid leukemia (AML PDX mouse model) and demonstrate that MS67, in contrast to an earlier WDR5 inhibitor (OICR-9429), effectively and selectively degrades WDR5, down-regulates the transcription of WDR5-regulated genes, decreases the chromatin-bound fraction of MLL complex components, suppresses cancer cell proliferation and the growth of tumors, and increases the lifespan of the animal models.

“MS67 represents a promising and specific WDR5 degrader that has potential for future therapeutic development,” the authors note.

These findings are reported in the Science Translational Medicine article, “A selective WDR5 degrader inhibits acute myeloid leukemia in patient-derived mouse models.” The research was supported in part by grants from the U.S. National Institutes of Health.

Jian Jin, PhD, professor of Therapeutics Discovery and director of the Mount Sinai Center for Therapeutics Discovery at the Icahn School of Medicine at Mount Sinai, is a senior author of the paper

“This study is the first to demonstrate that pharmacological degradation of WDR5, which selectively eliminates the protein, is an effective and superior therapeutic strategy than pharmacological inhibition, or blocking, of WDR5 for the treatment of WDR5-dependent cancers including acute myeloid leukemia with mixed lineage leukemia rearrangement,” says Jian Jin, PhD, professor of Therapeutics Discovery and director of the Mount Sinai Center for Therapeutics Discovery at the Icahn School of Medicine at Mount Sinai. “In addition, MS67 is the first WDR5 small-molecule degrader that exhibits robust anti-tumor activities in vivo.”

WDR5 drives the proliferation of other cancers such as pancreatic and breast cancer, leading researchers to believe that this potent and selective small-molecule degrader of WDR5, MS67, could be effective in treating other WDR5-dependent cancers as well.

As part of the design-directed approach, the authors decipher two high-resolution crystal structures of WDR5- degrader-E3 ligase ternary complexes. They design MS67 based on the crystal structure of an earlier WDR5 degrader in complex with WDR5 and the E3 ligase von Hippel–Lindau (VHL), and show the high cooperativity of MS67 binding to WDR5 and VHL by the biophysical characterization of another ternary complex structure.

“Our results demonstrate that structure-based design can be an effective strategy to identify highly active degraders,” the authors conclude.

In their next steps, the researchers intend to conduct studies to enable IND filing followed by first-time-in-human studies.

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