Identification of a New Heterocyclic Scaffold for Inhibitors of the Polo-Box Domain of Polo-like Kinase 1

Abstract

As a mitotic-specific target widely deregulated in various human cancers, polo-like kinase 1 (Plk1) has been extensively explored for anticancer activity and drug discovery. Although multiple catalytic domain inhibitors were tested in preclinical and clinical studies, their efficacies are limited by dose-limiting cytotoxicity, mainly from off-target cross reactivity. The Cterminal noncatalytic polo-box domain (PBD) of Plk1 has emerged as an attractive target for generating new protein−protein interaction inhibitors. Here, we identified a 1-thioxo-2,4-dihydro-[1,2,4]triazolo[4,3-a]quinazolin-5(1H)-one scaffold that efficiently inhibits Plk1 PBD but not its related Plk2 and Plk3 PBDs. Structure−activity relationship studies led to multiple inhibitors having ≥10-fold higher inhibitory activity than the previously characterized Plk1 PBD-specific phosphopeptide, PLHSpT (K d ∼ 450 nM). In addition, S-methyl prodrugs effectively inhibited mitotic progression and cell proliferation and their metabolic stability was determined. These data describe a novel class of small-molecule inhibitors that offer a promising avenue for future drug discovery against Plk1-addicted cancers.

Polo-like Kinase 1 Inhibitors in Human Cancer Therapy: Development and Therapeutic Potential

“…Alverez et al. found quinazolinone compound 59 (Figure B) with a higher affinity than the polypeptide PLHSpT . On the basis of thioxo-2,4-dihydro-[1,2,4]­triazolo-[4,3- a ]­quinazolin-5­(1 H )-one skeleton with 7-F substitution, they identified 60 and the cyclopropane-containing analogue 61 .…”

Novel Macrocyclic Peptidomimetics Targeting the Polo-Box Domain of Polo-Like Kinase 1

“…The resulting residue was subjected to flash column chromatography on silica gel (5% MeOH/CH 2 Cl 2 ) to afford 2 (0.74 g, 62% overall yield of 3 steps) as a white solid. 1 Methyl ((3S,6S,9S,17R,19S)-9-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-6-((benzyloxy)methyl)-3-((R)-1-((bis(benzyloxy)phosphoryl)oxy)ethyl)-2,5,8,12-tetraoxo-16-oxa-1,4,7,13tetraazabicyclo[15.2.1]icosane-19-carbonyl)-L-leucinate (14). To a solution of 1H-tetrazole (0.42 g, 6.02 mmol) in MeCN (13.39 mL), dibenzyl N,N-diisopropylphosphoramidite (90% tech.…”

“…Furthermore, it was reported that KBJK557, a barbiturate-fused pyrazole derivative derived by virtual screening, possesses a comparable IC 50 value (16.35 μM) to that of PLHSpT (29.02 μM) and exhibits a significant in vivo antitumorigenic effect upon intravenous administration . Also, 1-thioxo-2,4-dihydro-[1,2,4]­triazolo­[4,3- a ]­quinazolin-5­(1 H )-one derivatives have been reported to potently and selectively inhibit Plk1-PBD . Interestingly, it was recently reported that abbapolins, nonpeptidic Plk1 binding inhibitors, induce Plk1 degradation in prostate cancer cells .…”

“…13 Also, 1-thioxo-2,4-dihydro-[1,2,4]triazolo[4,3-a]quinazolin-5(1H)-one derivatives have been reported to potently and selectively inhibit Plk1-PBD. 14 Interestingly, it was recently reported that abbapolins, nonpeptidic Plk1 binding inhibitors, induce Plk1 degradation in prostate cancer cells. 15 However, extensive high-throughput screening has failed to identify PBD-targeting compounds that have high potency and specificity.…”

Regulation of the SIAH2-HIF-1 Axis by Protein Kinases and Its Implication in Cancer Therapy

“…Among them, GW843682 has the closest IC 50 level toward PLK3 compared to that of PLK1 (9.1 nM for PLK3 vs. 2.2 nM for PLK1) ( Murugan et al, 2011 ; Liu, 2015 ). Attempts to enhance the specificity toward PLKs over other kinases or PLK1 over other PLKs have been made to inhibit its PBD using small molecules, phosphopeptides, or using siRNA ( Kumar and Kim, 2015 ; Hymel et al, 2018 ; Alverez et al, 2020 ). For instance, small chemicals Poloxin and poloxipan inhibit the polo box of PLKs with the IC 50 ranging from 1.17 μM to 53.9 μM toward PLK 1/2/3.…”