title: CUDC-101, a multitargeted inhibitor of histone deacetylase, epidermal growth factor receptor, and human epidermal growth factor receptor 2, exerts potent anticancer activity.
abstract: Receptor tyrosine kinase inhibitors have recently become important therapeutics for a variety of cancers. However, due to the heterogeneous and dynamic nature of tumors, the effectiveness of these agents is often hindered by poor response rates and acquired drug resistance. To overcome these limitations, we created a novel small molecule, CUDC-101, which simultaneously inhibits histone deacetylase and the receptor kinases epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) in cancer cells. Because of its integrated histone deacetylase inhibition, CUDC-101 synergistically blocked key regulators of EGFR/HER2 signaling pathways, also attenuating multiple compensatory pathways, such as AKT, HER3, and MET, which enable cancer cells to escape the effects of conventional EGFR/HER2 inhibitors. CUDC-101 displayed potent antiproliferative and proapoptotic activities against cultured and implanted tumor cells that are sensitive or resistant to several approved single-targeted drugs. Our results show that CUDC-101 has the potential to dramatically improve the treatment of heterogeneous and drug-resistant tumors that cannot be controlled with single-target agents. Further, they provide a framework to create individual small molecules that simultaneously antagonize multiple biochemically distinct oncogenic targets, suggesting a general paradigm to surpass conventional, single-target cancer therapeutics. Cancer Res; 70(9); 3647-56. (c)2010 AACR.
authors.affiliation: Curis, Inc, Cambridge, Massachusetts, USA.
authors.forename: Cheng-Jung
authors.initials: CJ
authors.lastname: Lai
authors.forename: Rudi
authors.initials: R
authors.lastname: Bao
authors.forename: Xu
authors.initials: X
authors.lastname: Tao
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Ruzanna
authors.initials: R
authors.lastname: Atoyan
authors.forename: Hui
authors.initials: H
authors.lastname: Qu
authors.forename: Da-Gong
authors.initials: DG
authors.lastname: Wang
authors.forename: Ling
authors.initials: L
authors.lastname: Yin
authors.forename: Maria
authors.initials: M
authors.lastname: Samson
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Forrester
authors.forename: Brian
authors.initials: B
authors.lastname: Zifcak
authors.forename: Guang-Xin
authors.initials: GX
authors.lastname: Xu
authors.forename: Steven
authors.initials: S
authors.lastname: DellaRocca
authors.forename: Hai-Xiao
authors.initials: HX
authors.lastname: Zhai
authors.forename: Xiong
authors.initials: X
authors.lastname: Cai
authors.forename: William E
authors.initials: WE
authors.lastname: Munger
authors.forename: Mitchell
authors.initials: M
authors.lastname: Keegan
authors.forename: Carmen V
authors.initials: CV
authors.lastname: Pepicelli
authors.forename: Changgeng
authors.initials: C
authors.lastname: Qian
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D066246:ErbB Receptors; D047628:Estrogen Receptor alpha; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D051057:Proto-Oncogene Proteins c-akt; D019859:Proto-Oncogene Proteins c-met; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D017978:Receptors, Growth Factor; C549566:7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide; C491743:MET protein, human