Identification of a Bis-guanylhydrazone [4,4′-Diacetyldiphenylurea-bis(guanylhydrazone); NSC 109555] as a Novel Chemotype for Inhibition of Chk2 Kinase

Jobson, Andrew G.; Cardellina, John H.; Scudiero, Dominic A.; Kondapaka, Sudhir B.; Zhang, Hongliang; Kim, Hijoo; Shoemaker, Robert H.; Pommier, ﻿Yves

doi:10.1124/mol.107.035832

Cited by 54 publications

(57 citation statements)

References 37 publications

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“…29 The cocrystal structure of Chk2 with NSC 109555 confirms that the inhibitor interacts with the ATP-binding pocket in an elongated manner (see Fig. 2) but more importantly, the mode of binding differs from what had been previously predicted by molecular modeling.…”

Section: Binding Mode Of Nsc 109555mentioning

confidence: 75%

“…29) suggested that the guanidylhydrazone and urea groups are important for the activity of NSC 109555. With the availability of the cocrystal structure, it is now possible to correlate these studies with important aspects of the protein-inhibitor interactions.…”

Section: Binding Mode Of Nsc 109555mentioning

confidence: 99%

“…2) but more importantly, the mode of binding differs from what had been previously predicted by molecular modeling. 29 In the binding mode predicted by computational methods, the inhibitor adopted a ''horse-shoe'' conformation with hydrogen bonds to Leu226, Asp311, Asp328, and Glu351. The electron density maps, however, clearly reveal that NSC 109555 is anchored to the ATP-binding pocket in an extended conformation via hydrogen bonding of the guanidinium terminus to Glu273, which is located on the C-a helix (see Fig.…”

Section: Binding Mode Of Nsc 109555mentioning

confidence: 99%

“…1(A)], was recently identified by our laboratories using a highthroughput screening assay. 29 NSC 109555 is an ATPcompetitive inhibitor that represents a new chemotype for a Chk2 inhibitor with high potency (IC 50 ¼ 240 nM) and selectivity. Seeking to understand the mode of inhibition of Chk2 by NSC 109555, we cocrystallized the catalytic domain of Chk2 with the inhibitor and refined the structure to a resolution of 2.05 Å.…”

Section: Introductionmentioning

confidence: 99%

“…9,20,22 Additionally, because of the role of p53 in the initiation of apoptosis in response to DNA damage, inhibition of Chk2 in normal cells may also protect normal tissues, 1,23 which may reduce side effects due to chemotherapy or radiation therapy. 24 Because only a few specific inhibitors of Chk2 have been identified to date, [24][25][26][27][28][29][30] the discovery of additional inhibitors remains of considerable interest. A novel inhibitor of Chk2, NSC 109555 [ Fig.…”

Section: Introductionmentioning

confidence: 99%

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Crystal structure of checkpoint kinase 2 in complex with NSC 109555, a potent and selective inhibitor

et al. 2008

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Checkpoint kinase 2 (Chk2), a ser/thr kinase involved in the ATM-Chk2 checkpoint pathway, is activated by genomic instability and DNA damage and results in either arrest of the cell cycle to allow DNA repair to occur or apoptosis if the DNA damage is severe. Drugs that specifically target Chk2 could be beneficial when administered in combination with current DNAdamaging agents used in cancer therapy. Recently, a novel inhibitor of Chk2, NSC 109555, was identified that exhibited high potency (IC 50 = 240 nM) and selectivity. This compound represents a new chemotype and lead for the development of novel Chk2 inhibitors that could be used as therapeutic agents for the treatment of cancer. To facilitate the discovery of new analogs of NSC 109555 with even greater potency and selectivity, we have solved the crystal structure of this inhibitor in complex with the catalytic domain of Chk2. The structure confirms that the compound is an ATP-competitive inhibitor, as the electron density clearly reveals that it occupies the ATPbinding pocket. However, the mode of inhibition differs from that of the previously studied structure of Chk2 in complex with debromohymenialdisine, a compound that inhibits both Chk1 and Chk2. A unique hydrophobic pocket in Chk2, located very close to the bound inhibitor, presents an opportunity for the rational design of compounds with higher binding affinity and greater selectivity.

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Section: Binding Mode Of Nsc 109555mentioning

confidence: 75%

Section: Binding Mode Of Nsc 109555mentioning

confidence: 99%

Section: Binding Mode Of Nsc 109555mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Crystal structure of checkpoint kinase 2 in complex with NSC 109555, a potent and selective inhibitor

et al. 2008

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Divergent Synthesis and Evaluation of the in vitro Cytotoxicity Profiles of 3,4‐Ethylenedioxythiophenyl‐2‐propen‐1‐one Analogues

et al. 2019

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A new series of 3,4‐ethylenedioxythiophene (EDOT)‐appended propenones were prepared by condensation reaction and their in vitro cytotoxicity effects were evaluated against five human cancer cell lines. Preliminary structure–activity relationships of EDOT‐incorporated 2‐propenone derivatives were also established. The EDOT‐appended enones demonstrated significant cytotoxicity against human cancer cell lines. The most active analogue, (E)‐3‐(2,3‐dihydrothieno[3,4‐b][1,4]dioxin‐5‐yl)‐1‐(3,4,5‐trimethoxyphenyl)prop‐2‐en‐1‐one (3 p, GI50=110 nm), severely inhibited the clonogenic potential of cancer cells, and induced cell‐cycle arrest in the G2/M phase and caused an accumulation of HCT116 colon cancer cells with >4 N DNA content. Also, 3 p exhibited weak inhibition of the enzymatic activity of human topoisomerase I. Molecular docking studies indicated preferential binding of the compounds to the ATP‐binding pocket of the human checkpoint 2 kinase (Chk2) catalytic domain, thus, identifying a novel diaryl 2‐propenone chemotype for the development of potent inhibitors of Chk2.

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Synthesis, Characterization, Biological Activity and Molecular Modeling Studies of Novel Aminoguanidine Derivatives

Doğan¹,

Yavuz²,

Şahin

et al. 2022

ChemistrySelect

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In recent years, various compounds including the aminoguanidine scaffold have been reported to exhibit diverse biological activities. In the current study, 16 compounds that include guanylhydrazone (aminoguanidine) moiety (3 a-3 p) were synthesized and characterized through the spectrum data, including 1 H-NMR, 13 C-NMR, and FT-IR. Furthermore, the proposed structure of 3 a was resolved by single-crystal X-ray diffractometer. The prepared compounds were then tested for their different in vitro biological activities including antitumor activities against several types of cancer cell lines (A549, MCF-7, and U87-MG). Results showed that among the studied compounds especially 3 i, 3 n, and 3 p showed promising antiproliferative effect and they may be considered as good candidates for further in vitro and/or in vivo animal model studies. All the 16 derivatives synthesized in this study were also screened for their antimicrobial, antioxidant activity and DNA cleavage properties. Furthermore, multidimensional molecular modeling approaches were conducted for better understanding of their biological activities in atomic level.

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Identification of a Bis-guanylhydrazone [4,4′-Diacetyldiphenylurea-bis(guanylhydrazone); NSC 109555] as a Novel Chemotype for Inhibition of Chk2 Kinase

Cited by 54 publications

References 37 publications

Crystal structure of checkpoint kinase 2 in complex with NSC 109555, a potent and selective inhibitor

Crystal structure of checkpoint kinase 2 in complex with NSC 109555, a potent and selective inhibitor

Divergent Synthesis and Evaluation of the in vitro Cytotoxicity Profiles of 3,4‐Ethylenedioxythiophenyl‐2‐propen‐1‐one Analogues

Synthesis, Characterization, Biological Activity and Molecular Modeling Studies of Novel Aminoguanidine Derivatives

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