Bcl-2/MDM2 Dual Inhibitors Based on Universal Pyramid-Like α‑Helical Mimetics

No
α-helical mimetic that exhibits Bcl-2/MDM2 dual inhibition
has been rationally designed due to the different helicities of the
α-helixes at their binding interfaces. Herein, we extracted
a one-turn α-helix-mimicking ortho-triarene
unit from o-phenylene foldamers. Linking benzamide
substrates with a rotatable C–N bond, we constructed a novel
semirigid pyramid-like scaffold that could support its two-turn α-helix
mimicry without aromatic stacking interactions and could adopt the
different dihedral angles of the key residues of p53 and BH3-only
peptides. On the basis of this universal scaffold, a series of substituent
groups were installed to capture the key residues of both p53TAD and
BimBH3 and balance the differences of the bulks between them. Identified
by FP, ITC, and NMR spectroscopy, a compound 6e (zq-1) that directly binds to Mcl-1, Bcl-2, and
MDM2 with balanced submicromolar affinities was obtained. Cell-based
experiments demonstrated its antitumor ability through Bcl-2/MDM2
dual inhibition simultaneously.