Design, synthesis and biological activities of pyrrole-3-carboxamide derivatives as EZH2 (enhancer of zeste homologue 2) inhibitors and anticancer agents

Zhou, Qifan; Jia, Lei; Du, Fangyu; Dong, Xiaoyu; Sun, Wanyu; Wang, Lihui; Chen, Guoliang

doi:10.1039/c9nj04713a

Cited by 12 publications

(7 citation statements)

References 29 publications

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“…To assess the potential of the two selected compounds from the molecular docking simulations we identified for each of these compounds the specific interactions that they established with each of the proteins. We compared these data with information obtained from X-ray cocrystallised structures with known inhibitors as well as with results already gathered from the several molecular docking simulations performed by other groups to gain insight into EZH2 [ 34 , 35 , 36 , 37 , 38 , 39 , 40 ] and P20S inhibition [ 32 , 41 , 42 , 43 , 44 , 45 , 46 ].…”

Section: Resultsmentioning

confidence: 99%

Exploring EZH2-Proteasome Dual-Targeting Drug Discovery through a Computational Strategy to Fight Multiple Myeloma

et al. 2021

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Multiple myeloma is an incurable plasma cell neoplastic disease representing about 10–15% of all haematological malignancies diagnosed in developed countries. Proteasome is a key player in multiple myeloma and proteasome inhibitors are the current first-line of treatment. However, these are associated with limited clinical efficacy due to acquired resistance. One of the solutions to overcome this problem is a polypharmacology approach, namely combination therapy and multitargeting drugs. Several polypharmacology avenues are currently being explored. The simultaneous inhibition of EZH2 and Proteasome 20S remains to be investigated, despite the encouraging evidence of therapeutic synergy between the two. Therefore, we sought to bridge this gap by proposing a holistic in silico strategy to find new dual-target inhibitors. First, we assessed the characteristics of both pockets and compared the chemical space of EZH2 and Proteasome 20S inhibitors, to establish the feasibility of dual targeting. This was followed by molecular docking calculations performed on EZH2 and Proteasome 20S inhibitors from ChEMBL 25, from which we derived a predictive model to propose new EZH2 inhibitors among Proteasome 20S compounds, and vice versa, which yielded two dual-inhibitor hits. Complementarily, we built a machine learning QSAR model for each target but realised their application to our data is very limited as each dataset occupies a different region of chemical space. We finally proceeded with molecular dynamics simulations of the two docking hits against the two targets. Overall, we concluded that one of the hit compounds is particularly promising as a dual-inhibitor candidate exhibiting extensive hydrogen bonding with both targets. Furthermore, this work serves as a framework for how to rationally approach a dual-targeting drug discovery project, from the selection of the targets to the prediction of new hit compounds.

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Section: Resultsmentioning

confidence: 99%

Exploring EZH2-Proteasome Dual-Targeting Drug Discovery through a Computational Strategy to Fight Multiple Myeloma

et al. 2021

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“…In 2020, two series of derivatives were designed starting with compound 40 , structural simplification provided compound 41 , and insertion of an electron-donating group on the pyridine ring gave compound 42 . In compound 41 , the 6,5-fused indole scaffold was simplified to a five-membered pyrrole ring as a basic scaffold (Figure ). During the SAR development of compound 42 , an electron-donating thiomethyl group was attached with pyridone moiety to increase the population of desirable pyridone tautomer over hydroxypyridine.…”

Section: Sam-competitive Inhibitors Of Hkmtsmentioning

confidence: 99%

“…All previous identification of EZH2 screening hits and their subsequent optimization involved structurally related pyridones. Rao et al discovered the extremely potent and selective EZH2 inhibitor 47 bearing structurally unrelated chemotype tetramethylpiperidinyl benzamide scaffold and showing picomolar potency (IC 50 = 32 pM) against EZH2. , HTS campaign with a multistep triage process led to the discovery of a hit with micromolar potency, and optimization provided 47 as a potent and selective EZH2 inhibitor. , A SAM-competitive inhibitor, 47 showed a dose-dependent reduction in global levels of H3K27me3 in KARPAS-422 lymphoma cells. However, it also displayed a high efflux ratio in a Caco-2 assay, indicative of poor oral bioavailability, and this called for further optimization .…”

Section: Sam-competitive Inhibitors Of Hkmtsmentioning

confidence: 99%

Fascinating Transformation of SAM-Competitive Protein Methyltransferase Inhibitors from Nucleoside Analogues to Non-Nucleoside Analogues

2022

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The abnormal expression of protein methyltransferase (PMT) has been linked with many diseases such as diabetes, neurological disorders, and cancer. S-Adenyl-l-methionine (SAM) is a universal methyl donor and gets converted to S-adenyl-l-homocysteine (SAH), an endogenous competitive inhibitor of SAM. Initially developed SAM/SAH mimetic nucleoside analogues were pan methyltransferase inhibitors. The gradual understanding achieved through ligand–receptor interaction paved the way for various rational approaches of drug design leading to potent and selective nucleoside inhibitors. The present perspective is based on the systematic evolution of selective SAM-competitive heterocyclic non-nucleoside inhibitors from nucleoside inhibitors. This fascinating transition has resolved several issues inherent to nucleoside analogues such as poor pharmacokinetics leading to poor in vivo efficacy. The perspective has brought together various concepts and strategies of drug design that contributed to this rational transition. We firmly believe that the strategies described herein will serve as a template for the future development of drugs in general.

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“…Yellow solid (95% yield); m.p.222 °C. 1 1-(4-Amino-3-(1H-pyrrol-1-yl)phenyl)ethan-1-one (16). Orange oil (81% yield).…”

Section: -(5-isopropyl-2-nitrophenyl)-1h-pyrrolementioning

confidence: 99%

“…In particular, a set of pyrrole-3-carboxamide derivatives showed interesting antiproliferative effects in leukemia and pulmonary cell lines (such K562 and A549). e best compound 1 (Figure 1), derived from an intense structure-activity relationship (SAR) study, showed a low potency but high selectivity towards different tumor suppressors downstreams [16]. Furthermore, symmetrically substituted pyrroles were simply synthesized and evaluated as apoptotic agents in colorectal HCT116 and leukemic HL60 cells.…”

Section: Introductionmentioning

confidence: 99%

Green Synthesis of New Pyrrolo [1,2-a] quinoxalines as Antiproliferative Agents in GPER-expressing Breast Cancer Cells

Carullo

Giordano

Aiello

2021

Journal of Chemistry

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4,5-Dihydropyrrolo [1,2-a]quinoxalines are interesting druggable scaffolds, with multifaceted biological properties, including anticancer properties targeting the G protein-coupled estrogen receptor 1 (GPER). In this work, the synthesis and preliminary antiproliferative activity of a small set of new 4,5-dihydropyrrolo[1,2-a]quinoxalines (18-20) and pyrrolo[1,2-a]quinoxalines (21, 22) has been reported, inspired by known antiproliferative agents (G-1, G-15, and G-36). The synthesis of the pyrroloquinoxalinic core was employed following the Pictet–Spengler reaction, using the surfactant p-dodecylbenzene sulphonic acid (p-DBSA), as catalyst. It demonstrated efficiency in the catalysis of the 4-phenylpyrrole [1,2-a] quinoxaline type compound formation in mild solvents such as water, ethanol, and hydroalcoholic solutions. In addition, the reactions proceeded in a short time (between 15 and 120 minutes) at room temperature and with high yields. The in vitro MTT assays showed that the presence of isopropyl groups furnished promising antiproliferative compounds. Although, the acetyl group provided also antiproliferative effects, breaking down its responsibility in the GPER transactivation. Nevertheless, it is possible to conclude that the 4,5-dihydropyrrolo[1,2-a]quinoxalines remain a feasible scaffold to develop anticancer agents against GPER-expressing cells.

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Design, synthesis and biological activities of pyrrole-3-carboxamide derivatives as EZH2 (enhancer of zeste homologue 2) inhibitors and anticancer agents

Abstract: A novel series of pyrrole-3-carboxamides targeting EZH2 have been designed and synthesized. The structure–activity relationships were summarized by combining with in vitro biological activity assay and docking results.

Cited by 12 publications

References 29 publications

Exploring EZH2-Proteasome Dual-Targeting Drug Discovery through a Computational Strategy to Fight Multiple Myeloma

Exploring EZH2-Proteasome Dual-Targeting Drug Discovery through a Computational Strategy to Fight Multiple Myeloma

Fascinating Transformation of SAM-Competitive Protein Methyltransferase Inhibitors from Nucleoside Analogues to Non-Nucleoside Analogues

Green Synthesis of New Pyrrolo [1,2-a] quinoxalines as Antiproliferative Agents in GPER-expressing Breast Cancer Cells

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