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A novel small-molecule inhibitor of mcl-1 blocks pancreatic cancer growth in vitro and in vivo.

ABSTRACT: 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.

SUBMITTER: Abulwerdi F

PROVIDER: S-EPMC4174574 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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A novel small-molecule inhibitor of mcl-1 blocks pancreatic cancer growth in vitro and in vivo.

Abulwerdi Fardokht F Liao Chenzhong C Liu Meilan M Azmi Asfar S AS Aboukameel Amro A Mady Ahmed S A AS Gulappa Thippeswamy T Cierpicki Tomasz T Owens Scott S Zhang Tao T Sun Duxin D Stuckey Jeanne A JA Mohammad Ramzi M RM Nikolovska-Coleska Zaneta Z

Molecular cancer therapeutics 20130909 3

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 ...[more]

PMID: 24019208

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A novel small-molecule inhibitor of mcl-1 blocks pancreatic cancer growth in vitro and in vivo.

Publications

A novel small-molecule inhibitor of mcl-1 blocks pancreatic cancer growth in vitro and in vivo.

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