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3-(Indol-2-yl)indazoles as Chek1 kinase inhibitors: Optimization of potency and selectivity via substitution at C6.

Fraley ME, Steen JT, Brnardic EJ, Arrington KL, Spencer KL, Hanney BA, Kim Y, Hartman GD, Stirdivant SM, Drakas BA, Rickert K, Walsh ES, Hamilton K, Buser CA, Hardwick J, Tao W, Beck SC, Mao X, Lobell RB, Sepp-Lorenzino L, Yan Y, Ikuta M, Munshi SK, Kuo LC, Kreatsoulas C
Bioorg Med Chem Lett 16 6049-53 (2006)
Cited: 24 times
EuropePMC logo PMID: 16978863

Abstract

The development of 3-(indol-2-yl)indazoles as inhibitors of Chek1 kinase is described. Introduction of amides and heteroaryl groups at the C6 position of the indazole ring system provided sufficient Chek1 potency and selectivity over Cdk7 to permit escape from DNA damage-induced arrest in a cellular assay. Enzyme potency against Chek1 was optimized by the incorporation of a hydroxymethyl triazole moiety in compound 21 (Chek1 IC(50)=0.30nM) that was shown by X-ray crystallography to displace one of three highly conserved water molecules in the HI region of the ATP-binding cleft.

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  1. 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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  3. Discovery of novel checkpoint kinase 1 inhibitors by virtual screening based on multiple crystal structures. Li Y, Kim DJ, Ma W, Lubet RA, Bode AM, Dong Z. J Chem Inf Model 51 2904-2914 (2011)
  4. Structure-based predictions of activity cliffs. Husby J, Bottegoni G, Kufareva I, Abagyan R, Cavalli A. J Chem Inf Model 55 1062-1076 (2015)
  5. Development and validation of an improved algorithm for overlaying flexible molecules. Taylor R, Cole JC, Cosgrove DA, Gardiner EJ, Gillet VJ, Korb O. J Comput Aided Mol Des 26 451-472 (2012)
  6. A Comparative Study of Systems Pharmacology and Gene Chip Technology for Predicting Targets of a Traditional Chinese Medicine Formula in Primary Liver Cancer Treatment. Li S, Sun Y, Sun Y. Front Pharmacol 13 768862 (2022)
  7. Rapid Identification of Inhibitors and Prediction of Ligand Selectivity for Multiple Proteins: Application to Protein Kinases. Ma Z, Huang SY, Cheng F, Zou X. J Phys Chem B 125 2288-2298 (2021)


Reviews citing this publication (3)

  1. Synthesis of indazole motifs and their medicinal importance: an overview. Gaikwad DD, Chapolikar AD, Devkate CG, Warad KD, Tayade AP, Pawar RP, Domb AJ. Eur J Med Chem 90 707-731 (2015)
  2. Novel inhibitors of checkpoint kinase 1. Arrington KL, Dudkin VY. ChemMedChem 2 1571-1585 (2007)
  3. The hunt for antimitotic agents: an overview of structure-based design strategies. Dube D, Tiwari P, Kaur P. Expert Opin Drug Discov 11 579-597 (2016)

Articles citing this publication (13)

  1. Site-selective Suzuki-Miyaura coupling of heteroaryl halides - understanding the trends for pharmaceutically important classes. Almond-Thynne J, Blakemore DC, Pryde DC, Spivey AC. Chem Sci 8 40-62 (2017)
  2. Development of thioquinazolinones, allosteric Chk1 kinase inhibitors. Converso A, Hartingh T, Garbaccio RM, Tasber E, Rickert K, Fraley ME, Yan Y, Kreatsoulas C, Stirdivant S, Drakas B, Walsh ES, Hamilton K, Buser CA, Mao X, Abrams MT, Beck SC, Tao W, Lobell R, Sepp-Lorenzino L, Zugay-Murphy J, Sardana V, Munshi SK, Jezequel-Sur SM, Zuck PD, Hartman GD. Bioorg Med Chem Lett 19 1240-1244 (2009)
  3. A New Indole Derivative Decreased SALL4 Gene Expression in Acute Promyelocytic Leukemia Cell Line (NB4) Sheikhrezaei Z, Heydari P, Farsinezhad A, Fatemi A, Khanamani Falahati-Pour S, Darakhshan S, Noroozi Karimabad M, Darekordi A, Khorramdelazad H, Hassanshahi G. Iran Biomed J 22 99-106 (2018)
  4. SMT-A07, a 3-(Indol-2-yl) indazole derivative, induces apoptosis of leukemia cells in vitro. Qian S, Cao J, Yan Y, Sun M, Zhu H, Hu Y, He Q, Yang B. Mol Cell Biochem 345 13-21 (2010)
  5. Synthesis and biological evaluation of 4'-(6,7-disubstituted-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-biphenyl-4-ol as potent Chk1 inhibitors. Tao ZF, Li G, Tong Y, Chen Z, Merta P, Kovar P, Zhang H, Rosenberg SH, Sham HL, Sowin TJ, Lin NH. Bioorg Med Chem Lett 17 4308-4315 (2007)
  6. 1,4-Dihydroindeno[1,2-c]pyrazoles as potent checkpoint kinase 1 inhibitors: extended exploration on phenyl ring substitutions and preliminary ADME/PK studies. Tong Y, Claiborne A, Pyzytulinska M, Tao ZF, Stewart KD, Kovar P, Chen Z, Credo RB, Guan R, Merta PJ, Zhang H, Bouska J, Everitt EA, Murry BP, Hickman D, Stratton TJ, Wu J, Rosenberg SH, Sham HL, Sowin TJ, Lin NH. Bioorg Med Chem Lett 17 3618-3623 (2007)
  7. Macrocyclic ureas as potent and selective Chk1 inhibitors: an improved synthesis, kinome profiling, structure-activity relationships, and preliminary pharmacokinetics. Tao ZF, Chen Z, Bui MH, Kovar P, Johnson E, Bouska J, Zhang H, Rosenberg S, Sowin T, Lin NH. Bioorg Med Chem Lett 17 6593-6601 (2007)
  8. Computational fragment-based drug design to explore the hydrophobic sub-pocket of the mitotic kinesin Eg5 allosteric binding site. Oguievetskaia K, Martin-Chanas L, Vorotyntsev A, Doppelt-Azeroual O, Brotel X, Adcock SA, de Brevern AG, Delfaud F, Moriaud F. J Comput Aided Mol Des 23 571-582 (2009)
  9. Identification of novel inhibitors of Aurora A with a 3-(pyrrolopyridin-2-yl)indazole scaffold. Song P, Chen M, Ma X, Xu L, Liu T, Zhou Y, Hu Y. Bioorg Med Chem 23 1858-1868 (2015)
  10. Docking-based 3D-QSAR study of pyridyl aminothiazole derivatives as checkpoint kinase 1 inhibitors. Balupuri A, Balasubramanian PK, Gadhe CG, Cho SJ. SAR QSAR Environ Res 25 651-671 (2014)
  11. Synthesis and Biological Evaluation of Azamacrolide Comprising the Triazole Moiety as Quorum Sensing Inhibitors. Zhang B, Guo B, Bai Y, Lu H, Dong Y. Molecules 23 E1086 (2018)
  12. Synthesis, checkpoint kinase 1 inhibitory properties and in vitro antiproliferative activities of new pyrrolocarbazoles. Conchon E, Anizon F, Aboab B, Golsteyn RM, Léonce S, Pfeiffer B, Prudhomme M. Bioorg Med Chem 16 4419-4430 (2008)
  13. Tetrahydroindazole inhibitors of CDK2/cyclin complexes. Lee JC, Hong KH, Becker A, Tash JS, Schönbrunn E, Georg GI. Eur J Med Chem 214 113232 (2021)


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