Development of Novel Selective Peptidomimetics Containing a Boronic Acid Moiety, Targeting the 20S Proteasome as Anticancer Agents

Abstract

This paper describes the design, synthesis, and biological evaluation of peptidomimetic boronates as inhibitors of the 20S proteasome, a validated target in the treatment of multiple myeloma. The synthesized compounds showed a good inhibitory profile against the ChT-L activity of 20S proteasome. Compounds bearing a β-alanine residue at the P2 position were the most active, that is, 3-ethylphenylamino and 4-methoxyphenylamino (R)-1-{3-[4-(substituted)-2-oxopyridin-1(2H)-yl]propanamido}-3-methylbutylboronic acids (3 c and 3 d, respectively), and these derivatives showed inhibition constants (Ki ) of 17 and 20 nM, respectively. In addition, they co-inhibited post glutamyl peptide hydrolase activity (3 c, Ki=2.57 μM; 3 d, Ki=3.81 μM). No inhibition was recorded against the bovine pancreatic α-chymotrypsin, which thus confirms the selectivity towards the target enzyme. Docking studies of 3 c and related inhibitors into the yeast proteasome revealed the structural basis for specificity. The evaluation of growth inhibitory effects against 60 human tumor cell lines was performed at the US National Cancer Institute. Among the selected compounds, 3 c showed 50% growth inhibition (GI50) values at the sub-micromolar level on all cell lines.

Development of Novel Amides as Noncovalent Inhibitors of Immunoproteasomes

“…Splitting patterns are described as singlet (s), broad singlet (br s), doublet (d), triplet (t), quartet (q), multiplet (m), doublet of doublets (dd), doublet of doublets of doublets (ddd), or triplet of doublets (td). Compounds 27 – 30 were synthesized as previously reported …”

“…In this context, our research group has been actively involved in the development of novel 20S proteasome inhibitors . In particular, we have identified a series of amides, some of which were active against the chymotrypsin‐like activity of the 20S proteasome with K i values in the sub‐micromolar range. The noncovalent binding mode of the most active inhibitors was corroborated by docking simulations into the crystal structure of the yeast 20S proteasome.…”

Novel Class of Proteasome Inhibitors: In Silico and In Vitro Evaluation of Diverse Chloro(trifluoromethyl)aziridines

“…Docking results predicted promising activities as PIs ( Table 1 ). With these results in hand, we decided to evaluate the in vitro inhibitory activity of compounds 15 – 25 against the ChT-L activity of the human 20S proteasome [ 31 , 44 , 62 , 63 , 64 , 65 , 66 ]. The calculated free energies of binding (Δ G ) and the calculated and experimental Ki values at the binding site of the proteasome are reported in Table 1 .…”

Computational Approaches for the Discovery of Human Proteasome Inhibitors: An Overview

“…The biological evaluation of the compounds in the human 20S proteasome showed a promising inhibition profile, mainly for compounds bearing a P2 ethylene fragment ( K i values in the nM range for the CT-L active site). Docking experiments into the yeast 20S proteasome were performed according to a protocol previously applied by the same group [146] and showed that the ligands are accommodated mostly into the CT-L site, establishing a covalent bond with the catalytic Thr1 via the boron atom [145].…”