Discovery of an Oral, Beyond-Rule-of-Five Mcl‑1 Protein–Protein Interaction Modulator with the Potential of Treating Hematological Malignancies

Avoidance of apoptosis is critical for the development
and sustained
growth of tumors. The pro-survival protein myeloid cell leukemia 1
(Mcl-1) is an anti-apoptotic member of the Bcl-2 family of proteins
which is overexpressed in many cancers. Upregulation of Mcl-1 in human
cancers is associated with high tumor grade, poor survival, and resistance
to chemotherapy. Therefore, pharmacological inhibition of Mcl-1 is
regarded as an attractive approach to treating relapsed or refractory
malignancies. Herein, we disclose the design, synthesis, optimization,
and early preclinical evaluation of a potent and selective small-molecule
inhibitor of Mcl-1. Our exploratory design tactics focused on structural
modifications which improve the potency and physicochemical properties
of the inhibitor while minimizing the risk of functional cardiotoxicity.
Despite being in the “non-Lipinski” beyond-Rule-of-Five
property space, the developed compound benefits from exquisite oral
bioavailability in vivo and induces potent pharmacodynamic
inhibition of Mcl-1 in a mouse xenograft model.