TY - JOUR
T1 - Discovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors That Demonstrate in Vivo Activity in Mouse Xenograft Models of Human Cancer
AU - Lee, Taekyu
AU - Christov, Plamen P.
AU - Shaw, Subrata
AU - Tarr, James C.
AU - Zhao, Bin
AU - Veerasamy, Nagarathanam
AU - Jeon, Kyu Ok
AU - Mills, Jonathan J.
AU - Bian, Zhiguo
AU - Sensintaffar, John L.
AU - Arnold, Allison L.
AU - Fogarty, Stuart A.
AU - Perry, Evan
AU - Ramsey, Haley E.
AU - Cook, Rebecca S.
AU - Hollingshead, Melinda
AU - Davis Millin, Myrtle
AU - Lee, Kyung Min
AU - Koss, Brian
AU - Budhraja, Amit
AU - Opferman, Joseph T.
AU - Kim, Kwangho
AU - Arteaga, Carlos L.
AU - Moore, William J.
AU - Olejniczak, Edward T.
AU - Savona, Michael R.
AU - Fesik, Stephen W.
PY - 2019/4/25
Y1 - 2019/4/25
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.8b01991
DO - 10.1021/acs.jmedchem.8b01991
M3 - Article
C2 - 30929420
AN - SCOPUS:85064991352
VL - 62
SP - 3971
EP - 3988
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 8
ER -