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Development of 6-substituted indolylquinolinones as potent Chek1 kinase inhibitors.

Huang S, Garbaccio RM, Fraley ME, Steen J, Kreatsoulas C, Hartman G, Stirdivant S, Drakas B, Rickert K, Walsh E, Hamilton K, Buser CA, Hardwick J, Mao X, Abrams M, Beck S, Tao W, Lobell R, Sepp-Lorenzino L, Yan Y, Ikuta M, Murphy JZ, Sardana V, Munshi S, Kuo L, Reilly M, Mahan E
Bioorg Med Chem Lett 16 5907-12 (2006)
Related entries: 2hxq, 2hy0

Cited: 20 times
EuropePMC logo PMID: 16990002

Abstract

Through a comparison of X-ray co-crystallographic data for 1 and 2 in the Chek1 active site, it was hypothesized that the affinity of the indolylquinolinone series (2) for Chek1 kinase would be improved via C6 substitution into the hydrophobic region I (HI) pocket. An efficient route to 6-bromo-3-indolyl-quinolinone (9) was developed, and this series was rapidly optimized for potency by modification at C6. A general trend was observed among these low nanomolar Chek1 inhibitors that compounds with multiple basic amines, or elevated polar surface area (PSA) exhibited poor cell potency. Minimization of these parameters (basic amines, PSA) resulted in Chek1 inhibitors with improved cell potency, and preliminary pharmacokinetic data are presented for several of these compounds.

Articles - 2hxl mentioned but not cited (6)

  1. Predicting new indications for approved drugs using a proteochemometric method. Dakshanamurthy S, Issa NT, Assefnia S, Seshasayee A, Peters OJ, Madhavan S, Uren A, Brown ML, Byers SW. J Med Chem 55 6832-6848 (2012)
  2. DockBench: An Integrated Informatic Platform Bridging the Gap between the Robust Validation of Docking Protocols and Virtual Screening Simulations. Cuzzolin A, Sturlese M, Malvacio I, Ciancetta A, Moro S. Molecules 20 9977-9993 (2015)
  3. Identification of gefitinib off-targets using a structure-based systems biology approach; their validation with reverse docking and retrospective data mining. Verma N, Rai AK, Kaushik V, Brünnert D, Chahar KR, Pandey J, Goyal P. Sci Rep 6 33949 (2016)
  4. 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)
  5. Structure-based predictions of activity cliffs. Husby J, Bottegoni G, Kufareva I, Abagyan R, Cavalli A. J Chem Inf Model 55 1062-1076 (2015)
  6. 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. Novel inhibitors of checkpoint kinase 1. Arrington KL, Dudkin VY. ChemMedChem 2 1571-1585 (2007)
  2. Checkpoint kinase inhibitors: a patent review (2009 - 2010). Lainchbury M, Collins I. Expert Opin Ther Pat 21 1191-1210 (2011)
  3. Recent Advances in One-Pot Modular Synthesis of 2-Quinolones. Hong WP, Shin I, Lim HN. Molecules 25 E5450 (2020)

Articles citing this publication (11)

  1. 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)
  2. Discovery of 1,4-dihydroindeno[1,2-c]pyrazoles as a novel class of potent and selective checkpoint kinase 1 inhibitors. Tong Y, Claiborne A, Stewart KD, Park C, Kovar P, Chen Z, Credo RB, Gu WZ, Gwaltney SL, Judge RA, Zhang H, Rosenberg SH, Sham HL, Sowin TJ, Lin NH. Bioorg Med Chem 15 2759-2767 (2007)
  3. Optimization of a pyrazoloquinolinone class of Chk1 kinase inhibitors. Brnardic EJ, Garbaccio RM, Fraley ME, Tasber ES, Steen JT, Arrington KL, Dudkin VY, 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 17 5989-5994 (2007)
  4. Synthesis and biological evaluation of substituted 3-anilino-quinolin-2(1H)-ones as PDK1 inhibitors. O'Brien NJ, Brzozowski M, Wilson DJ, Deady LW, Abbott BM. Bioorg Med Chem 22 3781-3790 (2014)
  5. Synthesis and evaluation of substituted benzoisoquinolinones as potent inhibitors of Chk1 kinase. Garbaccio RM, Huang S, Tasber ES, Fraley ME, Yan Y, Munshi S, Ikuta M, Kuo L, Kreatsoulas C, Stirdivant S, Drakas B, Rickert K, Walsh ES, Hamilton KA, Buser CA, Hardwick J, Mao X, Beck SC, Abrams MT, Tao W, Lobell R, Sepp-Lorenzino L, Hartman GD. Bioorg Med Chem Lett 17 6280-6285 (2007)
  6. Discovery of the 1,7-diazacarbazole class of inhibitors of checkpoint kinase 1. Gazzard L, Appleton B, Chapman K, Chen H, Clark K, Drobnick J, Goodacre S, Halladay J, Lyssikatos J, Schmidt S, Sideris S, Wiesmann C, Williams K, Wu P, Yen I, Malek S. Bioorg Med Chem Lett 24 5704-5709 (2014)
  7. A general Pd/Cu-catalyzed C-H heteroarylation of 3-bromoquinolin-2(1H)-ones. Bruneau A, Brion JD, Messaoudi S, Alami M. Org Biomol Chem 12 8533-8541 (2014)
  8. Structural requirements of pyrimidine, thienopyridine and ureido thiophene carboxamide-based inhibitors of the checkpoint kinase 1: QSAR, docking, molecular dynamics analysis. Wang F, Ma Z, Li Y, Wang J, Wang Y. J Mol Model 18 3227-3242 (2012)
  9. Design and synthesis of a novel tyrosine kinase inhibitor template. Jake Slavish P, Jiang Q, Cui X, Morris SW, Webb TR. Bioorg Med Chem 17 3308-3316 (2009)
  10. Synthesis and preliminary structure-activity relationship study of 2-aryl-2H-pyrazolo[4,3-c]quinolin-3-ones as potential checkpoint kinase 1 (Chk1) inhibitors. Malvacio I, Cuzzolin A, Sturlese M, Vera DMA, Moyano EL, Moro S. J Enzyme Inhib Med Chem 33 171-183 (2017)
  11. Applications of NMR screening techniques to the pharmaceutical target Checkpoint kinase 1. Lancelot N, Piotto M, Theret I, Lesur B, Hennig P. J Pharm Biomed Anal 93 125-135 (2014)


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