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

Abstract

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.

Rationally Designed Polypharmacology: α‐Helix Mimetics as Dual Inhibitors of the Oncoproteins Mcl‐1 and HDM2

“…Both the Bim-BH3 and p53TAD α-helices project similar hydrophobic character at "hot spot" residues i, i + 3/4, and i + 7: Leu62, Ile65, and Phe69 in Bim ( Figure 1B), and Phe19, Trp23, and Leu26 in p53TAD ( Figure 1D). [44][45][46] Importantly, there is a conserved arginine residue on pro-life proteins (Arg263 in Mcl-1) that forms a salt bridge with Asp67 on the Bim α-helix at the i + 5 position. [47] Additionally, there is an aspartate residue in an analogous location (i + 2) in p53TAD (Asp21), that helps maintain the integrity of the helix rather than engage in recognition.…”

“…The most potent inhibitor of Bcl-2, Mcl-1, and HDM2 achieved affinities of K i = 0.140, 0.161, and 0.107 μM, respectively. [45] Leveraging the successes from Novartis and Zhang with heavily functionalized pyrazoles to inhibit the Bcl-2 family of proteins and HDM2, coupled with the effective deployment of the acyl sulfonamide functional group as a carboxylic acid bioisostere in Mcl-1 inhibitors elsewhere, we designed a library of three novel, densely functionalized scaffolds to mimic the BH3 binding domain and p53TAD: isoxazoles, pyrazoles, and thiazoles ( Figure 4, right structure), which are all present in pharmacologically active drug molecules. [52][53][54][55] Each scaffold will allow us to explore the protein binding interfaces with different substitution patterns: isoxazoles represent a 1,2,3-functionalization (with the numbering starting with the acyl substituent), pyrazoles represent a 1,3,4-functionalization, and thiazoles a 1,2,4-functionalization.…”

“…This superior functionality is present in both the Novartis patent and the Zhang et al dual inhibitor. [45,51] We hypothesized that the conversion of the carboxylic acid to an acyl sulfonamide would offer greater inhibition, accom- Table 1. Inhibition of Mcl-1 and HDM2 with isoxazoles, pyrazoles, and thiazoles using fluorescence anisotropy competition assay (FACA).…”

Design, syntheses and antitumor activities evaluation of 1,5‐diaryl substituted pyrazole secnidazole ester derivatives

“…1 The pyrazole is just one of such species. They have shown extensive bioactivities, 2 such as anti-tumor, 3 antimicrobial, 4 antifungal, 5 hypoglycemic, 6 anti-inflammatory, 7 analgesic, 8 against oxidative stress and diabetes, 9 and various enzyme inhibiting activities, 10 etc. In particular, promising potentials against the malignant tumor have been demonstrated in some of modified pyrazole derivatives when they were grafted with other active groups according to the drug hybridization principle.…”

Cell‐ and Tissue‐Based Proteome Profiling and Dual Imaging of Apoptosis Markers with Probes Derived from Venetoclax and Idasanutlin

“…[2] Currently,v enetoclax has been approved and idasanutlin (RG7388) is under clinical investigation. These agents are used to treat acute myeloid leukemia (AML) and neuroblastoma, respectively.B cl-2 family proteins and MDM2 interact similarly with p53TAD, [3] thus providing opportunities for dual Bcl-2/ MDM2 targeting with ac ombination of venetoclax with idasanutlin as an effective therapeutic strategy.R ecently, several groups have reported that these two drugs used together for the treatment of p53 wild-type acute myeloid leukemia and neuroblastoma [4] show highly synergistic antitumor activity as compared to treatment with either drug as as ingle agent. Pan et al presented am echanism for the synergistic effect in AML.…”