当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Discovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors That Demonstrate in Vivo Activity in Mouse Xenograft Models of Human Cancer.

Discovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors That Demonstrate in Vivo Activity in Mouse Xenograft Models of Human Cancer.

Abstract：

:Overexpression of myeloid cell leukemia-1 (Mcl-1) in cancers correlates with high tumor grade and poor survival. Additionally, Mcl-1 drives intrinsic and acquired resistance to many cancer therapeutics, including B cell lymphoma 2 family inhibitors, proteasome inhibitors, and antitubulins. Therefore, Mcl-1 inhibition could serve as a strategy to target cancers that require Mcl-1 to evade apoptosis. Herein, we describe the use of structure-based design to discover a novel compound (42) that robustly and specifically inhibits Mcl-1 in cell culture and animal xenograft models. Compound 42 binds to Mcl-1 with picomolar affinity and inhibited growth of Mcl-1-dependent tumor cell lines in the nanomolar range. Compound 42 also inhibited the growth of hematological and triple negative breast cancer xenografts at well-tolerated doses. These findings highlight the use of structure-based design to identify small molecule Mcl-1 inhibitors and support the use of 42 as a potential treatment strategy to block Mcl-1 activity and induce apoptosis in Mcl-1-dependent cancers.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Lee T,Christov PP,Shaw S,Tarr JC,Zhao B,Veerasamy N,Jeon KO,Mills JJ,Bian Z,Sensintaffar JL,Arnold AL,Fogarty SA,Perry E,Ramsey HE,Cook RS,Hollingshead M,Davis Millin M,Lee KM,Koss B,Budhraja A,Opferman JT,Kim K

doi

10.1021/acs.jmedchem.8b01991

subject

Has Abstract

pub_date

2019-04-25 00:00:00

pages

3971-3988

issue

8

eissn

0022-2623

issn

1520-4804

journal_volume

62

pub_type

杂志文章

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