Discovery and in Vivo Evaluation of Macrocyclic Mcl‑1 Inhibitors Featuring an α‑Hydroxy Phenylacetic Acid Pharmacophore or Bioisostere

Overexpression of the antiapoptotic protein Mcl-1 provides
a survival
advantage to some cancer cells, making inhibition of this protein
an attractive therapeutic target for the treatment of certain types
of tumors. Herein, we report our efforts toward the identification
of a novel series of macrocyclic Mcl-1 inhibitors featuring an α-hydroxy
phenylacetic acid pharmacophore or bioisostere. This work led to the
discovery of 1, a potent Mcl-1 inhibitor (IC50 = 19 nM in an OPM-2 cell viability assay) with good pharmacokinetic
properties and excellent in vivo efficacy in an OPM-2 multiple myeloma
xenograft model.