Multi-target inhibitor targeting HDAC, EGFR and HER2
Form:
Free acid
Research Area:
Breast cancer,gastric cancer, head and neck cancer
REVIEW CUDC-101 is a potent inhibitor of histone deacetylase (HDAC) and the receptor kinases epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), with IC50 values of 4.4, 2.4, and 15.7 nM, respectively. It inhibted EGFR and Her2 phosphorylation, reduced cell proliferation and induced apoptosis in HCC827 non-small cell lung cancer (NSCLC) xenografts. CUDC-101 inhibited EGFR and induced upregulation of acetylated histone H3 in a dose-dependent fashion. CUDC-101 is efficacious in EGFR inhibitor sensitive and resistant NSCLC cell lines and xenografts. CUDC-101 is also efficacious in epidermoid, pancreatic, and hepatocellular cancer cell lines and xenografts. In addition to CUDC-101 inhibited histone deacetylase and synergistically blocked key regulators of EGFR/HER2 signaling pathways. It also attenuated multiple compensatory pathways including AKT, HER3, and MET, which enable cancer cells to escape the effects of conventional EGFR/HER2 inhibitors. CUDC-101 might improve the treatment of tumors that cannot be controlled with single-target agents. CUDC-101 inhibited the proliferation of most tumor cell lines tested with greater potency than vorinostat (SAHA), erlotinib, lapatinib, and combinations of vorinostat/erlotinib and vorinostat/lapatinib. In vivo, CUDC-101 promoted tumor regression in various cancer xenograft models such as non-small cell lung cancer (NSCLC), liver, breast, head and neck, colon, and pancreatic cancers.
REFERENCES
[1]
Qian, Changgeng; Cai, Xiong; Gould, Stephen; Zhai, Haixiao; Preparation of quinazoline based EGFR inhibitors containing a zinc binding moiety, PCT Int. Appl. (2008), WO 2008033749 A2 20080320.
[2]
Cai X, Zhai HX, Wang J, Forrester J, Qu H, Yin L, Lai CJ, Bao R, Qian C. Discovery of 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide (CUDc-101) as a potent multi-acting HDAC, EGFR, and HER2 inhibitor for the treatment of cancer. J Med Chem. 2010 Mar 11;53(5):2000-9.
[3]
Lai CJ, Bao R, Tao X, Wang J, Atoyan R, Qu H, Wang DG, Yin L, Samson M, Forrester J, Zifcak B, Xu GX, DellaRocca S, Zhai HX, Cai X, Munger WE, Keegan M, Pepicelli CV, Qian C. CUDC-101, a multitargeted inhibitor of histone deacetylase, epidermal growth factor receptor, and human epidermal growth factor receptor 2, exerts potent anticancer activity. Cancer Res. 2010 May 1;70(9):3647-56.
[4]
Wang J, Pursell NW, Samson ME, Atoyan R, Ma AW, Selmi A, Xu W, Cai X, Voi M, Savagner P, Lai CJ. Potential advantages of CUDC-101, a multitargeted HDAC, EGFR, and HER2 inhibitor, in treating drug resistance and preventing cancer cell migration and invasion. Mol Cancer Ther. 2013 Jun;12(6):925-36.
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