Discovery of Macrocyclic Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors that Demonstrate Potent Cellular Efficacy and In Vivo Activity in a Mouse Solid Tumor Xenograft Model

The B cell lymphoma
2 (Bcl-2) family of proteins are key regulators
of intrinsic apoptosis. The antiapoptotic protein myeloid cell leukemia
1 (Mcl-1), which is associated with high tumor grade, poor survival,
and resistance to treatment, has emerged as a promising candidate
for treating hematological and solid cancers. Herein, we report the
structure-guided design of small molecule macrocyclic Mcl-1 inhibitors
based on the (R)-methyl-dihydropyrazinoindolone scaffold
our group has previously disclosed. The macrocyclic inhibitors bind
Mcl-1 with subnanomolar affinity and offer improved potency in cell
culture growth inhibition assays. Inhibitor 13 achieved
tumor regression in a lung cancer-derived tumor xenograft model in
mice as a monotherapy. The improved potency of the macrocyclic series
allowed replacement of heretofore conserved indole carboxylic acid
moiety, resulting in neutral inhibitors. Amide inhibitor 25 displayed a >10-fold increase in oral bioavailability as compared
to acid-containing macrocyclic or acyclic inhibitors.