Abstract
Breast cancer is one of the most lethal cancers in women when it reaches the metastatic stage. Here, we screen a library of small molecules for inhibitors of breast cancer cell invasion, and use structure/activity relationship studies to develop a series of small molecules with improved activity. We find WJ460 as one of the lead compounds exerting anti-metastatic activity in the nanomolar range in breast cancer cells. Proteomic and biochemical studies identify myoferlin (MYOF) as the direct target of WJ460. In parallel, loss of MYOF or pharmacological inhibition of MYOF by WJ460 reduces breast cancer extravasation into the lung parenchyma in an experimental metastasis mouse model, which reveals an essential role of MYOF in breast cancer progression. Our findings suggest that MYOF can be explored as a molecular target in breast cancer metastasis and that targeting MYOF by WJ460 may be a promising therapeutic strategy in MYOF-driven cancers.
Highlights
Breast cancer is one of the most lethal cancers in women when it reaches the metastatic stage
Research has revealed that MYOF functions in breast cancer invasion and epithelial-to-mesenchymal transition (EMT), suggesting that MYOF may act as a modifier of breast cancer metastasis[13,14,15]
The results indicated that the length of methylene chain greatly affected the inhibitory activity; the lead compound WJ460 with four methylene chain was established as the most effective inhibitor among the investigated compounds (Fig. 1b, c; and the synthesis scheme is shown in Supplementary Fig. 1, 2)
Summary
Breast cancer is one of the most lethal cancers in women when it reaches the metastatic stage. Therapies developed to target phosphoinositide-3 kinase/AKT/mammalian target of rapamycin signaling significantly improved disease-free survival[5] Other therapeutics such as cyclin-dependent kinase 4/6 inhibitors showed promising antitumor activity in a phase III clinical trial examining patients with hormone receptor-positive metastatic breast cancer that had progressed on prior endocrine therapy[6]. MK-3475, an anti-PD1 antibody, showed therapeutic activity in patients with recurrent/metastatic triple-negative breast cancer (TNBC) in a phase I clinical study[8]. These therapies are developed to perturb neoplastic growth, and despite the progress they made in metastatic breast cancer therapy, many patients will experience treatment failure. Our results demonstrated that WJ460 can serve as a first lead compound for the development of MYOF-targeted therapeutic agents and targeting MYOF by WJ460 may be a promising therapeutic strategy in MYOF-driven breast cancer
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