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Discovery of novel frizzled-7 inhibitors by targeting the receptor's transmembrane domain.

ABSTRACT: Frizzled (Fzd) proteins are seven transmembrane receptors that belong to a novel and separated family of G-protein-coupled receptors (GPCRs). The Fzd receptors can respond to Wnt proteins to activate the canonical ?-catenin pathway which is important for both initiation and progression of cancers. Disruption of the Wnt/?-catenin signal thus represents an opportunity for rational cancer prevention and therapy. Of the 10 members of the Fzd family, Fzd7 is the most important member involved in cancer development and progression. In the present studies, we applied structure-based virtual screening targeting the transmembrane domain (TMD) of Fzd7 to select compounds that could potentially bind to the Fzd7-TMD and block the Wnt/Fzd7 signaling and further evaluated them in biological assays. Six small molecule compounds were confirmed as Fzd7 inhibitors. The best hit, SRI37892, significantly blocked the Wnt/Fzd7 signaling with IC50 values in the sub-micromolar range and inhibited cancer cell proliferation with IC50 values around 2 ?M. Our results provide the first proof of concept of targeting Fzd-TMD for the development of Wnt/Fzd modulators. The identified small molecular Fzd7 inhibitors can serve as a useful tool for studying the regulation mechanism(s) of Wnt/Fzd7 signaling as well as a starting point for the development of cancer therapeutic agents.

SUBMITTER: Zhang W

PROVIDER: S-EPMC5710937 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Discovery of novel frizzled-7 inhibitors by targeting the receptor's transmembrane domain.

Zhang Wei W Lu Wenyan W Ananthan Subramaniam S Suto Mark J MJ Li Yonghe Y

Oncotarget 20170906 53

Frizzled (Fzd) proteins are seven transmembrane receptors that belong to a novel and separated family of G-protein-coupled receptors (GPCRs). The Fzd receptors can respond to Wnt proteins to activate the canonical β-catenin pathway which is important for both initiation and progression of cancers. Disruption of the Wnt/β-catenin signal thus represents an opportunity for rational cancer prevention and therapy. Of the 10 members of the Fzd family, Fzd7 is the most important member involved in canc ...[more]

PMID: 29207657

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Project description:To minimize treatment toxicities, recent anti-cancer research efforts have switched from broad-based chemotherapy to targeted therapy, and emerging data show that altered cellular metabolism in cancerous cells can be exploited as new venues for targeted intervention. In this study, we focused on, among the altered metabolic processes in cancerous cells, altered glycosylation due to its documented roles in cancer tumorigenesis, metastasis and drug resistance. We hypothesize that the enzymes required for the biosynthesis of UDP-hexoses, glycosyl donors for glycan synthesis, could serve as therapeutic targets for cancers. Through structure-based virtual screening and kinetic assay, we identified a drug-like chemical fragment, GAL-012, that inhibit a small family of UDP-hexose pyrophosphorylases-galactose pyro-phosphorylase (GALT), UDP-glucose pyrophosphorylase (UGP2) and UDP-N-acetylglucosamine pyrophosphorylase (AGX1/UAP1) with an IC50 of 30 µM. The computational docking studies supported the interaction of GAL-012 to the binding sites of GALT at Trp190 and Ser192, UGP2 at Gly116 and Lys127, and AGX1/UAP1 at Asn327 and Lys407, respectively. One of GAL-012 derivatives GAL-012-2 also demonstrated the inhibitory activity against GALT and UGP2. Moreover, we showed that GAL-012 suppressed the growth of PC3 cells in a dose-dependent manner with an EC50 of 75 µM with no effects on normal skin fibroblasts at 200 µM. Western blot analysis revealed reduced expression of pAKT (Ser473), pAKT (Thr308) by 77% and 72%, respectively in the treated cells. siRNA experiments against the respective genes encoding the pyrophosphorylases were also performed and the results further validated the proposed roles in cancer growth inhibition. Finally, synergistic relationships between GAL-012 and tunicamycin, as well as bortezomib (BTZ) in killing cultured cancer cells were observed, respectively. With its unique scaffold and relatively small size, GAL-012 serves as a promising early chemotype for optimization to become a safe, effective, multi-target anti-cancer drug candidate which could be used alone or in combination with known therapeutics.

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Discovery of novel frizzled-7 inhibitors by targeting the receptor's transmembrane domain.

Publications

Discovery of novel frizzled-7 inhibitors by targeting the receptor's transmembrane domain.

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