jm8b01991_si_002.csv (5.46 kB)
Discovery of Potent Myeloid Cell Leukemia‑1 (Mcl-1) Inhibitors That Demonstrate in Vivo Activity in Mouse Xenograft Models of Human Cancer
dataset
posted on 2019-03-30, 00:00 authored by Taekyu Lee, Plamen P. Christov, Subrata Shaw, James C. Tarr, Bin Zhao, Nagarathanam Veerasamy, Kyu Ok Jeon, Jonathan J. Mills, Zhiguo Bian, John L. Sensintaffar, Allison L. Arnold, Stuart A. Fogarty, Evan Perry, Haley E. Ramsey, Rebecca S. Cook, Melinda Hollingshead, Myrtle Davis Millin, Kyung-min Lee, Brian Koss, Amit Budhraja, Joseph T. Opferman, Kwangho Kim, Carlos L. Arteaga, William J. Moore, Edward T. Olejniczak, Michael R. Savona, Stephen W. FesikOverexpression
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.
