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Modeling ErbB2-p130Cas interaction to design new potential anticancer agents.

ABSTRACT: The ErbB2 receptor tyrosine kinase is overexpressed in approximately 15-20% of breast tumors and associated with aggressive disease and poor clinical outcome. p130Cas represents a nodal scaffold protein regulating cell survival, migration and proliferation in normal and pathological contexts. p130Cas overexpression in ErbB2 human breast cancer correlates with poor prognosis and metastasis formation. Recent data indicate that p130Cas association to ErbB2 protects ErbB2 from degradation, thus enhancing tumorigenesis. Therefore, inhibiting p130Cas/ErbB2 interaction might represent a new therapeutic strategy to target breast cancer. Here we demonstrate by performing Molecular Modeling, Molecular Dynamics, dot blot, ELISA and fluorescence quenching experiments, that p130Cas binds directly to ErbB2. Then, by structure-based virtual screening, we identified two potential inhibitors of p130Cas/ErbB2 interaction. Their experimental validation was performed in vitro and in ErbB2-positive breast cancer cellular models. The results highlight that both compounds interfere with p130Cas/ErbB2 binding and significantly affect cell proliferation and sensitivity to Trastuzumab. Overall, this study identifies p130Cas/ErbB2 complex as a potential breast cancer target revealing new therapeutic perspectives for protein-protein interaction (PPI).

SUBMITTER: Costamagna A

PROVIDER: S-EPMC6395809 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Modeling ErbB2-p130Cas interaction to design new potential anticancer agents.

Costamagna Andrea A Rossi Sebastiano Matteo M Natalini Dora D Simoni Matilde M Valabrega Giorgio G Defilippi Paola P Visentin Sonja S Ermondi Giuseppe G Turco Emilia E Caron Giulia G Cabodi Sara S

Scientific reports 20190228 1

The ErbB2 receptor tyrosine kinase is overexpressed in approximately 15-20% of breast tumors and associated with aggressive disease and poor clinical outcome. p130Cas represents a nodal scaffold protein regulating cell survival, migration and proliferation in normal and pathological contexts. p130Cas overexpression in ErbB2 human breast cancer correlates with poor prognosis and metastasis formation. Recent data indicate that p130Cas association to ErbB2 protects ErbB2 from degradation, thus enha ...[more]

PMID: 30816273

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Project description:Cancer is a large group of diseases in which the rapid proliferation of abnormal cells generally leads to metastasis to surrounding tissues or more distant ones through the lymphatic and blood vessels, making it the second leading cause of death worldwide. The main challenge in designing a modern anticancer therapy is to develop selective compounds that exploit specific molecular targets. In this work, novel oxazolo[5,4-d]pyrimidine derivatives were designed, synthesized, and evaluated in vitro for their cytotoxic activity against a panel of four human cancer cell lines (lung carcinoma: A549, breast adenocarcinoma: MCF7, metastatic colon adenocarcinoma: LoVo, primary colon adenocarcinoma: HT29), along with their P-glycoprotein-inhibitory ability and pro-apoptotic activity. These oxazolo[5,4-d]pyrimidine derivatives, which are structurally similar to nucleic purine bases in general, are characterized by the presence of a pharmacologically favorable isoxazole substituent at position 2 and aliphatic amino chains at position 7 of the condensed heterocyclic system. In silico analysis of the obtained compounds identified their potent inhibitory activity towards human vascular endothelial growth factor receptor-2 (VEGFR-2). Molecular docking was performed to assess the binding mode of new derivatives to the VEGFR-2 active site. Then, their physicochemical, pharmacokinetic, and pharmacological properties (i.e., ADME-administration, distribution, metabolism, and excretion) were also predicted to assess their druglikeness. In particular, compound 3g (with a 3-(N,N-dimethylamino)propyl substituent) was found to be the most potent against the HT29 cell line, with a 50% cytotoxic concentration (CC50) of 58.4 µM, exceeding the activity of fluorouracil (CC50 = 381.2 μM) and equaling the activity of cisplatin (CC50 = 47.2 µM), while being less toxic to healthy human cells (such as normal human dermal fibroblasts (NHDFs)) than these reference drugs. The results suggest that compound 3g is a potentially promising candidate for the treatment of primary colorectal cancer.

Dataset Information

Modeling ErbB2-p130Cas interaction to design new potential anticancer agents.

Publications

Modeling ErbB2-p130Cas interaction to design new potential anticancer agents.

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