Significant advancement towards specialized molecular therapies for cancer

Two recent studies signify a considerable progression towards the formulation of groundbreaking molecular therapies aimed at halting the unregulated expansion of cancers at their origins.

In a duo of manuscripts released in Nature, a group of researchers guided by Harvard’s Department of Chemistry and Chemical Biology (CCB) has illustrated how both small molecules and genetic alterations can modify the same vital protein interactions in cancer cells. These investigations shed light on two domains: identifying new “molecular glues” and comprehending the ramifications of genetic mutations within cancer cells, paving the way for therapeutic strategies.

“Our investigation has focused on deciphering how particular mutations in medulloblastoma, a pediatric brain malignancy, simulate the function of ‘molecular glues’ to propel oncogenic mechanisms,” stated senior author Brian Liau, associate professor of chemistry and chemical biology. “Throughout these studies, we’ve elucidated the convergence of genetic alterations and chemical modalities that modify protein interactions.”

Molecular glues are small molecules that compel two proteins that typically do not interact to connect. This action activates a cell’s inherent “waste disposal mechanism” to eliminate one of the proteins. Researchers have been investigating the potential of utilizing molecular glues to target disease-related proteins.

Previously, many of these interactions were neglected due to their intricacy and difficulty in identification. However, this research reveals a novel scaffold and mechanism that can be employed to invent molecular glues aimed at affecting specific protein interactions and functions.

This undertaking was led by members of Liau’s laboratory, including co-authors Megan Yeo, Olivia Zhang, Ceejay Lee, Idris Barakat, and Nicholas Chen (all Ph.D. candidates in the Griffin Graduate School of Arts and Sciences in CCB); postdoctoral fellows Jiaming Lee, Pallavi Gosavi, Hui Si Kwok, Stefan Harry, and Amanda Waterbury, along with research assistant Irtiza Iram. Additional contributions came from scientists at Harvard Medical School, the Broad Institute, the University of Washington, and St. Jude Children’s Research Hospital.

One investigation analyzed how molecular glues modify essential protein interaction networks. The researchers demonstrated that the compound UM171 functions as a glue that can initiate the breakdown of the CoREST complex, a regulatory system that governs gene access. UM171 operates by binding to a protein known as histone deacetylase (HDAC), part of a larger complex with CoREST, and attaching it to another protein called KBTBD4, which acts as an effector enzyme in protein degradation. These discoveries reveal new avenues for glues to be employed in targeting proteins that have traditionally been deemed undruggable, like CoREST, introducing innovative strategies for drug development.

“Understanding how this small molecule operates was a significant question in the field because previously no one was certain it was a molecular glue,” remarked Zhang. “We approached this issue using a multidisciplinary methodology, integrating both functional genomics and structural biology to yield new insights.”

In the companion investigation, the researchers examined cancer-promoting mutations in the KBTBD4 protein, which is frequently altered in a specific type of brain cancer. These mutations can transform normal cellular interactions into detrimental ones by modifying how proteins bind, resulting in inappropriate degradation of the CoREST complex.

The team successfully pinpointed which mutations in KBTBD4 are associated with cancer. They utilized cryo-electron microscopy (cryo-EM) to “visualize” these mutations at the atomic scale. By merging these techniques, the team uncovered that cancer mutations modify protein structure and function, reflecting the interaction between UM171 and KBTBD4.

“It’s incredibly challenging to conceive of what these insertion mutations actually accomplish without a structure because they occur in a flexible region of the protein, so having the cryo-EM structure was highly beneficial,” Yeo commented. “It was remarkable to observe the direct overlay of the small molecule and these cancer mutations, which we could not have envisioned without this technology.”

A key characteristic of this research was its emphasis on “convergence,” where a small molecule and a genetic mutation functionally and structurally replicate the effects of one another.

Within Liau’s laboratory, the researchers examined how comprehending one mechanism can guide the development and application of the other.

“Finding these types of molecular glue compounds is quite difficult, so if you could actually employ genetics to search for them, it would be very advantageous,” Liau noted. “This chemical-genetic convergence represents a new paradigm.”

Going forward, Liau’s lab intends to further investigate these molecular strategies, seeking additional instances of genetic mutations that can induce new protein interactions to facilitate chemical design. The ramifications of this research present a fresh approach toward understanding and targeting proteins for small molecule drug development.

“I’m enthusiastic about the potential trajectories our research may undertake,” Liau expressed. “The implications extend beyond cancer, potentially transforming our strategies for investigating a range of diseases.”

The study highlighted in this narrative received financial backing from the National Institute of General Medical Sciences and the National Institutes of Health’s National Cancer Institute.