Discovery of S64315, a Potent and Selective Mcl‑1 Inhibitor

Myeloid cell leukemia 1 (Mcl-1) has
emerged as an attractive target
for cancer therapy. It is an antiapoptotic member of the Bcl-2 family
of proteins, whose upregulation in human cancers is associated with
high tumor grade, poor survival, and resistance to chemotherapy. Here
we report the discovery of our clinical candidate S64315, a selective
small molecule inhibitor of Mcl-1. Starting from a fragment derived
lead compound, we have conducted structure guided optimization that
has led to a significant (3 log) improvement of target affinity as
well as cellular potency. The presence of hindered rotation along
a biaryl axis has conferred high selectivity to the compounds against
other members of the Bcl-2 family. During optimization, we have also
established predictive PD markers of Mcl-1 inhibition and achieved
both efficient in vitro cell killing and tumor regression in Mcl-1
dependent cancer models. The preclinical candidate has drug-like properties
that have enabled its development and entry into clinical trials.