Papers published in Cell Reports and Journal of Medicinal Chemistry suggest that targeted degradation by increasing ubiquitination of proteins that promote cancer could be a more complete strategy to treat cancer than catalytic inhibition.
As increased expression of enhancer of zeste homolog 2 (EZH2) has been shown to promote multiple types of cancer, EZH2 enzymatic inhibitors have been explored as cancer therapies. However, studies have shown blocking EZH2 enzyme function was insufficient to inhibit proliferation of some cancer cells, suggesting that increased elimination of EZH2 could be more efficacious.
In the Cell Reports paper, researchers at University of Texas MD Anderson Cancer Center suggest that inhibiting the deubiquitinase zinc finger RANBP2-type containing 1 (ZRANB1) could help treat breast cancer by degrading EZH2.
The MD Anderson scientists first showed that ZRANB1 overexpression decreased EZH2 ubiquitination and increased EZH2 protein levels. They also found that high levels of ZRANB1 in tissue from patients with breast cancer was associated with high levels of EZH2 and lower overall survival.
In mouse and human breast cancer cell cultures, siRNA knockdown of ZRANB1 or a tool compound that inhibits ZRANB1 decreased cell proliferation and increased apoptosis compared with control siRNA or vehicle.
In a mouse model of triple-negative breast cancer, anti-ZRANB1 siRNA decreased tumor growth and metastases to the lung.
In the Journal of Medicinal Chemistry paper, researchers at Dana-Farber Cancer Institute suggested that increasing ubiquitination of anaplastic lymphoma kinase (ALK) could help treat cancer.
The researchers chemically linked the ALK inhibitors Zykadia ceritinib or its parent compound, TAE684, to pomalidomide to recruit the E3 ubiquitin ligase cereblon (CRBN) to ALK.
In lung cancer and lymphoma cell cultures, the conjugated molecules decreased cell proliferation compared with the unconjugated ALK inhibitors alone.
Lead author Nathanael Gray is a founder of C4 Therapeutics (Cambridge, Mass.), one of several companies developing products for targeted protein degradation (see BioCentury Innovations, Nov. 2, 2017).
Novartis AG (NYSE:NVS; SIX:NOVN) and the Helsinn Therapeutics Inc. subsidiary of Helsinn Healthcare S.A. (Lugano, Switzerland) market Zykadia to treat non-small cell lung cancer (NSCLC).