%0 Generic
%A Lee, Taekyu
%A Christov, Plamen P.
%A Shaw, Subrata
%A Tarr, James C.
%A Zhao, Bin
%A Veerasamy, Nagarathanam
%A Jeon, Kyu Ok
%A Mills, Jonathan J.
%A Bian, Zhiguo
%A Sensintaffar, John L.
%A Arnold, Allison L.
%A Fogarty, Stuart A.
%A Perry, Evan
%A E. Ramsey, Haley
%A S. Cook, Rebecca
%A Hollingshead, Melinda
%A Davis Millin, Myrtle
%A Lee, Kyung-min
%A Koss, Brian
%A Budhraja, Amit
%A T. Opferman, Joseph
%A Kim, Kwangho
%A Arteaga, Carlos L.
%A Moore, William J.
%A Olejniczak, Edward T.
%A Savona, Michael R.
%A Fesik, Stephen W.
%D 2019
%T Discovery of Potent
Myeloid Cell Leukemia‑1
(Mcl-1) Inhibitors That Demonstrate in Vivo Activity in Mouse Xenograft
Models of Human Cancer
%U https://acs.figshare.com/articles/dataset/Discovery_of_Potent_Myeloid_Cell_Leukemia_1_Mcl-1_Inhibitors_That_Demonstrate_in_Vivo_Activity_in_Mouse_Xenograft_Models_of_Human_Cancer/8001296
%R 10.1021/acs.jmedchem.8b01991.s002
%2 https://acs.figshare.com/ndownloader/files/14897321
%K myeloid cell leukemia
%K structure-based design
%K B cell lymphoma 2 family inhibitors
%K Mcl -1-dependent cancers
%K breast cancer xenografts
%K Compound 42
%K Mcl -1-dependent tumor cell lines
%K Human Cancer Overexpression
%K Mouse Xenograft Models
%K animal xenograft models
%X 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.
%I ACS Publications