A Novel Small-Molecule Inhibitor of Mcl-1 Blocks Pancreatic Cancer Growth In Vitro and In Vivo

• Published in: Molecular cancer therapeutics Vol. 13; no. 3; pp. 565 - 575
• Main Authors: Abulwerdi, Fardokht, Liao, Chenzhong, Liu, Meilan, Azmi, Asfar S., Aboukameel, Amro, Mady, Ahmed S.A., Gulappa, Thippeswamy, Cierpicki, Tomasz, Owens, Scott, Zhang, Tao, Sun, Duxin, Stuckey, Jeanne A., Mohammad, Ramzi M., Nikolovska-Coleska, Zaneta
• Format: Journal Article
• Language: English
• Published: United States 01.03.2014
• Subjects: Animals; Apoptosis - drug effects; bcl-2 Homologous Antagonist-Killer Protein - chemistry; bcl-2 Homologous Antagonist-Killer Protein - genetics; bcl-2-Associated X Protein - chemistry; bcl-2-Associated X Protein - genetics; Cell Line, Tumor; Cell Proliferation - drug effects; Dimerization; Humans; Lead - administration & dosage; Mice; Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors; Myeloid Cell Leukemia Sequence 1 Protein - chemistry; Myeloid Cell Leukemia Sequence 1 Protein - genetics; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Sulfonamides - administration & dosage; Thioglycolates - administration & dosage; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514; 1538-8514
• DOI: 10.1158/1535-7163.MCT-12-0767

Using a high-throughput screening (HTS) approach, we have identified and validated several small-molecule Mcl-1 inhibitors (SMI). Here, we describe a novel selective Mcl-1 SMI inhibitor, 2 (UMI-77), developed by structure-based chemical modifications of the lead compound 1 (UMI-59). We have characterized the binding of UMI-77 to Mcl-1 by using complementary biochemical, biophysical, and computational methods and determined its antitumor activity against a panel of pancreatic cancer cells and an in vivo xenograft model. UMI-77 binds to the BH3-binding groove of Mcl-1 with Ki of 490 nmol/L, showing selectivity over other members of the antiapoptotic Bcl-2 family. UMI-77 inhibits cell growth and induces apoptosis in pancreatic cancer cells in a time- and dose-dependent manner, accompanied by cytochrome c release and caspase-3 activation. Coimmunoprecipitation experiments revealed that UMI-77 blocks the heterodimerization of Mcl-1/Bax and Mcl-1/Bak in cells, thus antagonizing the Mcl-1 function. The Bax/Bak-dependent induction of apoptosis was further confirmed using murine embryonic fibroblasts that are Bax- and Bak-deficient. In an in vivo BxPC-3 xenograft model, UMI-77 effectively inhibited tumor growth. Western blot analysis in tumor remnants revealed enhancement of proapoptotic markers and significant decrease of survivin. Collectively, these promising findings show the therapeutic potential of Mcl-1 inhibitors against pancreatic cancer and warrant further preclinical investigations. Mol Cancer Ther; 13(3); 565–75. ©2013 AACR.