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. 2020 Sep 16;15(18):1691-1698.
doi: 10.1002/cmdc.202000278. Epub 2020 Jun 25.

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

Ivie L Conlon  1 , Brandon Drennen  1 , Maryanna E Lanning  1 , Samuel Hughes  2 , Rebecca Rothhaas  1 , Paul T Wilder  3 , Alexander D MacKerell Jr  1 , Steven Fletcher  1
Affiliations

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

Ivie L Conlon et al. ChemMedChem. .

Abstract

Protein-protein interactions (PPIs), many of which are dominated by α-helical recognition domains, play key roles in many essential cellular processes, and the dysregulation of these interactions can cause detrimental effects. For instance, aberrant PPIs involving the Bcl-2 protein family can lead to several diseases including cancer, neurodegenerative diseases, and diabetes. Interactions between Bcl-2 pro-life proteins, such as Mcl-1, and pro-death proteins, such as Bim, regulate the intrinsic pathway of apoptosis. p53, a tumor-suppressor protein, also has a pivotal role in apoptosis and is negatively regulated by its E3 ubiquitin ligase HDM2. Both Mcl-1 and HDM2 are upregulated in numerous cancers, and, interestingly, there is crosstalk between both protein pathways. Recently, synergy has been observed between Mcl-1 and HDM2 inhibitors. Towards the development of new anticancer drugs, we herein describe a polypharmacology approach for the dual inhibition of Mcl-1 and HDM2 by employing three densely functionalized isoxazoles, pyrazoles, and thiazoles as mimetics of key α-helical domains of their partner proteins.

Keywords: apoptosis; cancer; heterocycles; polypharmacology; protein-protein interactions.

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Conflict of interest statement

Conflict of Interest: ADM Jr. is co-founder and Chief Scientific Officer of SilcsBio LLC

Figures

Figure 1.
Figure 1.
A) Co-crystal structure of Bim-BH3 bound to Mcl-1 (PDB ID: 2NL9), B) hot spot residues highlighted in Bim-BH3 peptide, C) co-crystal structure of p53TAD bound to HDM2 (PDB ID: 1YCR), D) hot spot residues highlighted in p53TAD.
Figure 2.
Figure 2.
Nutlin 3a (right) co-crystallized with HDM2 (PDB ID: 4J3E).
Figure 3.
Figure 3.
Co-crystal structure of Novartis compound and HDM2 (PDB ID: 4OQ3).
Figure 4.
Figure 4.
Representative structures of Novartis patent CA2771936A1 (left), Zhang et al. Dual Bcl-2/HDM2 inhibitor (center), and our work presented in this manuscript (right).
Figure 5.
Figure 5.
Energy minimization of OX0 in ChemDraw3D and overlaid with Bim-BH3 (center) and p53TAD (right) α-helices.
Figure 6.
Figure 6.
SILCS MC docking with OX0 in Mcl-1 (A, top) and HDM2 (B, below).
Figure 7.
Figure 7.
OX0 docked in Mcl-1 (left) and HDM2 (right) with SILCS. FragMaps (left).
Scheme 1.
Scheme 1.
(i) NaN3, DMF, r.t., 18hr; (ii) (4-OiPr)benzaldehyde, NaH, EtOH, −10°C, 4hr; (iii) NH2OH·HCl, Pyridine, reflux, 1hr; (iv) Et3N, NCS, DMF, rt to 90°C, 18hr; (v) LiOH·H2O, THF/MeOH/H2O, r.t.,18hr; (vi)corresponding sulfonamide, isobutyl chloroformate, NMM, NaH, THF, −10°C to 0°C to r.t., 18hr.
Scheme 2.
Scheme 2.
(ia) 2-iodopropane, K2CO3, DMF, r.t. to 60°C, 18hr; (ib) SnCl2·2H2O, EtOAc, 50°C, 18hr; (iia) NaNO2, H2O, 0°C, 18hr; (iib) SnCl2·2H2O, EtOAc, 50°C, o.n.; (iii) corresponding alcohol, K2CO3, DMF, 60°C, 18hr; (iv) diethyl oxalate, NaH, THF, 0°C to rt, 18hr; (v) AcOH, reflux, 18hr; (vi) LiOH·H2O, THF/MeOH/H2O, r.t., 18hr; (vii) corresponding sulfonamide, isobutyl chloroformate, NMM, NaH, THF, −10°C to 0°C to r.t., 18hr.
Scheme 3.
Scheme 3.
(i) NCS, ACN, 80°C, 18hr; (ii) t-BnONO, CuBr2, ACN, 80°C, 18hr; (iii) 4-hydroxyphenylboronic acid, CsF, tetrakis ((triphenylphosphine)palladium(0)), DME/MeOH, 80°C, 18hr;(iv) 2-iodopropane, K2CO3, DMF, 50°C, 18hr; (v) LiOH·H2O, THF/MeOH/H2O, r.t., 18hr; (vi) corresponding sulfonamide, isobutyl chloroformate, NMM, NaH, THF, −10° to 0°C to r.t., 18hr.
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