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

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.