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

Lountos GT, Tropea JE, Zhang D, Jobson AG, Pommier Y, Shoemaker RH, Waugh DS
Protein Sci 18 92-100 (2009)
Cited: 21 times
EuropePMC logo PMID: 19177354

Abstract

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 DNA-damaging 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 ATP-binding 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.

Articles - 2w0j mentioned but not cited (6)

  1. Cellular inhibition of checkpoint kinase 2 (Chk2) and potentiation of camptothecins and radiation by the novel Chk2 inhibitor PV1019 [7-nitro-1H-indole-2-carboxylic acid {4-[1-(guanidinohydrazone)-ethyl]-phenyl}-amide]. Jobson AG, Lountos GT, Lorenzi PL, Llamas J, Connelly J, Cerna D, Tropea JE, Onda A, Zoppoli G, Kondapaka S, Zhang G, Caplen NJ, Cardellina JH, Yoo SS, Monks A, Self C, Waugh DS, Shoemaker RH, Pommier Y. J Pharmacol Exp Ther 331 816-826 (2009)
  2. Crystal structure of checkpoint kinase 2 in complex with NSC 109555, a potent and selective inhibitor. Lountos GT, Tropea JE, Zhang D, Jobson AG, Pommier Y, Shoemaker RH, Waugh DS. Protein Sci 18 92-100 (2009)
  3. Benzimidazole inhibitors of the protein kinase CHK2: clarification of the binding mode by flexible side chain docking and protein-ligand crystallography. Matijssen C, Silva-Santisteban MC, Westwood IM, Siddique S, Choi V, Sheldrake P, van Montfort RL, Blagg J. Bioorg Med Chem 20 6630-6639 (2012)
  4. Effect of Binding Pose and Modeled Structures on SVMGen and GlideScore Enrichment of Chemical Libraries. Xu D, Meroueh SO. J Chem Inf Model 56 1139-1151 (2016)
  5. Genotoxicity of Novel Pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine Sulfonamides in Normal and Cancer Cells In Vitro. Kciuk M, Mujwar S, Marciniak B, Gielecińska A, Bukowski K, Mojzych M, Kontek R. Int J Mol Sci 24 4053 (2023)
  6. Discovery of New Protein Targets of BPA Analogs and Derivatives Associated with Noncommunicable Diseases: A Virtual High-Throughput Screening. Montes-Grajales D, Morelos-Cortes X, Olivero-Verbel J. Environ Health Perspect 129 37009 (2021)


Reviews citing this publication (3)

  1. DNA Damage Signalling and Repair Inhibitors: The Long-Sought-After Achilles' Heel of Cancer. Velic D, Couturier AM, Ferreira MT, Rodrigue A, Poirier GG, Fleury F, Masson JY. Biomolecules 5 3204-3259 (2015)
  2. ATM, ATR, CHK1, CHK2 and WEE1 inhibitors in cancer and cancer stem cells. Ronco C, Ronco C, Martin AR, Demange L, Benhida R. Medchemcomm 8 295-319 (2017)
  3. Structure-based design, discovery and development of checkpoint kinase inhibitors as potential anticancer therapies. Matthews TP, Jones AM, Collins I. Expert Opin Drug Discov 8 621-640 (2013)

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  1. The ability to enhance the solubility of its fusion partners is an intrinsic property of maltose-binding protein but their folding is either spontaneous or chaperone-mediated. Raran-Kurussi S, Waugh DS. PLoS One 7 e49589 (2012)
  2. Functional Analysis Identifies Damaging CHEK2 Missense Variants Associated with Increased Cancer Risk. Boonen RACM, Wiegant WW, Celosse N, Vroling B, Heijl S, Kote-Jarai Z, Mijuskovic M, Cristea S, Solleveld-Westerink N, van Wezel T, Beerenwinkel N, Eeles R, Devilee P, Vreeswijk MPG, Marra G, van Attikum H. Cancer Res 82 615-631 (2022)
  3. Inhibition of Oncogenic Kinases: An In Vitro Validated Computational Approach Identified Potential Multi-Target Anticancer Compounds. Ikram N, Mirza MU, Vanmeert M, Froeyen M, Salo-Ahen OMH, Tahir M, Qazi A, Ahmad S. Biomolecules 9 E124 (2019)
  4. Structural characterization of inhibitor complexes with checkpoint kinase 2 (Chk2), a drug target for cancer therapy. Lountos GT, Jobson AG, Tropea JE, Self CR, Zhang G, Pommier Y, Shoemaker RH, Waugh DS. J Struct Biol 176 292-301 (2011)
  5. The heterogenic final cell cycle of chicken retinal Lim1 horizontal cells is not regulated by the DNA damage response pathway. Shirazi Fard S, All-Ericsson C, Hallböök F. Cell Cycle 13 408-417 (2014)
  6. (10Z)-Debromohymenialdisine from Marine Sponge Stylissa sp. Regulates Intestinal Inflammatory Responses in Co-Culture Model of Epithelial Caco-2 Cells and THP-1 Macrophage Cells. Lee SM, Kim NH, Lee S, Kim YN, Heo JD, Rho JR, Jeong EJ. Molecules 24 E3394 (2019)
  7. Synthesis and evaluation of debromohymenialdisine-derived Chk2 inhibitors. Saleem RS, Lansdell TA, Tepe JJ. Bioorg Med Chem 20 1475-1481 (2012)
  8. Fragment-based screening maps inhibitor interactions in the ATP-binding site of checkpoint kinase 2. Silva-Santisteban MC, Westwood IM, Boxall K, Brown N, Peacock S, McAndrew C, Barrie E, Richards M, Mirza A, Oliver AW, Burke R, Hoelder S, Jones K, Aherne GW, Blagg J, Collins I, Garrett MD, van Montfort RL. PLoS One 8 e65689 (2013)
  9. Targeting of Chk2 as a countermeasure to dose-limiting toxicity triggered by topoisomerase-II (TOP2) poisons. Gokare P, Navaraj A, Zhang S, Motoyama N, Sung SS, Finnberg NK. Oncotarget 7 29520-29530 (2016)
  10. X-ray structures of checkpoint kinase 2 in complex with inhibitors that target its gatekeeper-dependent hydrophobic pocket. Lountos GT, Jobson AG, Tropea JE, Self CR, Zhang G, Pommier Y, Shoemaker RH, Waugh DS. FEBS Lett 585 3245-3249 (2011)
  11. Design checkpoint kinase 2 inhibitors by pharmacophore modeling and virtual screening techniques. Wang YL, Lin CY, Shih KC, Huang JW, Tang CY. Bioorg Med Chem Lett 23 6286-6291 (2013)
  12. Novel design strategy for checkpoint kinase 2 inhibitors using pharmacophore modeling, combinatorial fusion, and virtual screening. Lin CY, Wang YL. Biomed Res Int 2014 359494 (2014)


Related citations provided by authors (1)

  1. Identification of a Bis-guanylhydrazone [4,4'-Diacetyldiphenylurea-bis(guanylhydrazone); NSC 109555] as a novel chemotype for inhibition of Chk2 kinase.. Jobson AG, Cardellina JH, Scudiero D, Kondapaka S, Zhang H, Kim H, Shoemaker R, Pommier Y Mol Pharmacol 72 876-84 (2007)

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