Discovery of 2‑Indole-acylsulfonamide Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods

Myeloid cell leukemia-1 (Mcl-1) is
a member of the Bcl-2 family
of proteins responsible for the regulation of programmed cell death.
Amplification of Mcl-1 is a common genetic aberration in human cancer
whose overexpression contributes to the evasion of apoptosis and is
one of the major resistance mechanisms for many chemotherapies. Mcl-1
mediates its effects primarily through interactions with pro-apoptotic
BH3 containing proteins that achieve high affinity for the target
by utilizing four hydrophobic pockets in its binding groove. Here
we describe the discovery of Mcl-1 inhibitors using fragment-based
methods and structure-based design. These novel inhibitors exhibit
low nanomolar binding affinities to Mcl-1 and >500-fold selectivity
over Bcl-xL. X-ray structures of lead Mcl-1 inhibitors when complexed
to Mcl-1 provided detailed information on how these small-molecules
bind to the target and were used extensively to guide compound optimization.