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New York University (NYU) scientists and the New York University School of Medicine have used computer-based simulation tools to develop a new type of compound that blocks the interaction of the proteins involved in the development of drug-resistant prostate cancer. Rather than targeting the androgen receptor (AR), the primary therapeutic target for prostate cancer, the new compound is designed to block the interaction between two proteins of the Wnt signaling pathway, which is commonly mutated in patients' tumors. with metastatic prostate cancer. . Early in vitro and in vivo tests showed that the peptoid macrocycle inhibited Wnt signaling by blocking the interaction between ß-catenin and TCF (T-cell factor) transcription factors and inhibited proliferation of prostate cancer cells up to 39 to 95%.
"Rather than continue to make compounds that look like older drugs, our job has been to rethink the definition of what a drug-like molecule may be," says the author's correspondent Susan Logan, Ph.D. D., Associate Professor, Department of Urology, NYU School of Medicine. "We designed our peptoids specifically to hit currently" unbearable "targets, such as those causing treatment-resistant prostate cancer," says Kent Kirshenbaum, lead author, Ph.D., NYU professor of chemistry. .
The researchers report on the development of the compound, Nature Communications, in an article entitled "Peptoid-peptide macrocycle design to inhibit the interaction of β-catenin and TCF in prostate cancer".
Prostate cancer is the third leading cause of cancer-related mortality, and although patients with localized disease have a good prognosis, the 5-year survival rate of those with metastatic disease is only 30%, the authors write. . Most anticancer drugs target the androgen receptor (AR), but the majority of anti-androgen-treated patients will eventually become resistant to treatment and their disease will progress to metastatic castration-resistant prostate cancer (mCRPC).
In the search for alternative targets for prostate cancer, the researchers studied Wnt signaling, involved in the control of androgen receptor transcription. Studies have suggested that the Wnt signaling pathway is mutated in more than 20% of patients with mCRPC. The binding of β-catenin to the TCF family of transcription factors, which activates genes involved in cell proliferation and differentiation, is at the heart of Wnt signaling. However, as the team notes, "the Wnt path remains an enticing but difficult target for drug discovery."
The authors go on to explain that protein-protein (PPI) interactions constitute the structural and functional basis of many essential biological processes, but the design of molecules capable of inhibiting PPIs involved in the pathogenesis of the disease is not easy. . "Small molecules may not have enough surface to effectively abrogate protein-protein binding, as these interfaces are usually broad and flat," the team notes. "In addition, peptides often lack desirable pharmacological characteristics and are easily susceptible to degradation. in vivo. "
Some of these problems can be solved by designing peptidomimetic oligomers, which, according to the researchers, could represent an "attractive intermediate ground" between small molecules and large biomolecules. Foldamers, including a class of molecules called peptoids, for example, are sequence-specific oligomers that can be designed to mimic secondary structure forms of biomolecules and could represent potential therapeutic candidates. However, the design of these molecules represents what the team recognizes as a "formidable and intriguing challenge".
The team used computer-based protein design methods to generate peptoid-macrocyclic peptide hybrids that would target a portion of the β-catenin molecule by folding into complementary structures at a portion of its surface interacting with TCF, to prevent the interactions of the two proteins. .
The approach actually involved joining the ends of a linear peptoid to form cyclic structures, which resemble hairpins that TCFs depend on to interact with ß-catenin. The most promising of them, which the team called macrocycle 13, inhibits Wnt and AR signaling in cultured cells and directly blocks the β-catenin protein interaction: TCF.
Tests have shown that the compound blocks the proliferation of prostate cancer cells in vitro, 95%, compared to untreated cancer cells, whereas the linear peptoid reduced cell growth by only 40%. In vivo Experiments conducted in a zebrafish model showed that the compound inhibited Wnt signaling without harming the development of the zebrafish embryo. This zebrafish model exhibits hyperactive Wnt signaling and ß-catenin accumulation that prevents the eyes and forebrain from developing. The treatment with peptoids macrocycles saved the development of the eye by blocking the hyperactive interactions ß-catenin: TCF.
In vitro experiments have also shown that macrocycle peptoids lead to a reduction in the expression of the target gene of the RA pathway, which, according to the researchers, could be the result of a direct inhibition of the β-catenin interaction: AR or indirectly through the reduction of Wnt signaling, which then decreases AR gene transcripts.
They recognize that additional tests in prostate cancer models in mouse xenograft will be required to determine the therapeutic potential of macrocycle 13, or modified versions of the compound. "In this study, we show how computer tools can facilitate the design of oligomers that target β-catenin and disrupt its interaction with TCF," the authors say. "More generally, this study suggests a computer-assisted discovery of increasingly complex folded oligomers to address the large number of different PPIs relevant to human disease."
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