Discovery of the 1,7-diazacarbazole class of inhibitors of checkpoint kinase 1

Bioorganic and Medicinal Chemistry Letters

Volumn 24, Issue 24, 2014, Pages 5704-5709

  Gazzard, Lewis ^a   Appleton, Brent ^a   Chapman, Kerry ^b   Chen, Huifen ^a   Clark, Kevin ^a   Drobnick, Joy ^a   Goodacre, Simon ^b   Halladay, Jason ^a   Lyssikatos, Joseph ^a   Schmidt, Stephen ^a   Sideris, Steve ^a   Wiesmann, Christian ^a   Williams, Karen ^b   Wu, Ping ^a   Yen, Ivana ^a   Malek, Shiva ^a  

^a GENENTECH INC   (United States)

^b CHARLES RIVER LABORATORIES   (United Kingdom)

Author keywords

Checkpoint; ChK1; Diazacarbazole; GNE 783; Structure based design

Indexed keywords

1,7 DIAZACARBAZOLE DERIVATIVE; CARBAZOLE DERIVATIVE; CHECKPOINT KINASE 1; CYTOTOXIC AGENT; GEMCITABINE; GNE 783; PROTEIN SERINE THREONINE KINASE INHIBITOR; UNCLASSIFIED DRUG; CARBOLINE DERIVATIVE; DEOXYCYTIDINE; GNE-783; HETEROCYCLIC COMPOUND; PROTEIN KINASE; PROTEIN KINASE INHIBITOR;

ANIMAL EXPERIMENT; ANTIPROLIFERATIVE ACTIVITY; AREA UNDER THE CURVE; ARTICLE; BIOCHEMICAL COMPOSITION; COMPUTER MODEL; CONTROLLED STUDY; DOSE RESPONSE; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG CYTOTOXICITY; DRUG HALF LIFE; DRUG IDENTIFICATION; DRUG POTENCY; DRUG POTENTIATION; DRUG SOLUTION; DRUG SYNTHESIS; HIGH THROUGHPUT SCREENING; IC50; MAXIMUM PLASMA CONCENTRATION; MOLECULAR DOCKING; MOUSE; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION; SUSPENSION; X RAY CRYSTALLOGRAPHY; ANALOGS AND DERIVATIVES; ANIMAL; CHEMISTRY; DRUG DEVELOPMENT; HUMAN; ORAL DRUG ADMINISTRATION; PROTEIN CONFORMATION; SYNTHESIS; TISSUE DISTRIBUTION;

ADMINISTRATION, ORAL; ANIMALS; AZA COMPOUNDS; CARBAZOLES; CARBOLINES; CRYSTALLOGRAPHY, X-RAY; DEOXYCYTIDINE; DRUG DISCOVERY; DRUG SYNERGISM; HUMANS; MICE; PROTEIN CONFORMATION; PROTEIN KINASE INHIBITORS; PROTEIN KINASES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; TISSUE DISTRIBUTION;

EID: 84911921375     PISSN: 0960894X     EISSN: 14643405     Source Type: Journal    
DOI: 10.1016/j.bmcl.2014.10.063     Document Type: Article

References (22)

1. L. Carrassa, and G. Damia Cell Cycle 10 2011 2121
2. R. Thompson, and A. Eastman Br. J. Clin. Pharmacol. 76 2013 358
3. C.X. Ma, J.W. Janetka, and H. Piwnica-Worms Trends Mol. Med. 17 2011 88
4. A.N. Tse, R. Carvajal, and G.K. Schwartz Clin. Cancer Res. 2007 1955 13
5. C.X. Ma, S. Cai, S. Li, C.E. Ryan, Z. Guo, W.T. Schaiff, L. Lin, J. Hoog, R.J. Goiffon, A. Prat, R.L. Aft, M.J. Ellis, and H. Piwnica-Worms J. Clin. Invest. 122 2012 1541
6. E. Blackwood, J. Epler, I. Yen, M. Flagella, T. O'Brien, M. Evangelista, S. Schmidt, Y. Xiao, J. Choi, K. Kowanetz, J. Ramiscal, K. Wong, D. Jakubiak, S. Yee, G. Cain, L. Gazzard, K. Williams, J. Halladay, P.K. Jackson, and S. Malek Mol. Cancer Ther. 2013 1968 12
7. Unless stated otherwise Chk1 biochemical data refers to AlphaScreen assay data. Details of the ChK1 Z-lyte and AlphaScreen in vitro biochemical assays are given in Supplemental material.
8. A.L. Hopkins, C.R. Groom, and A. Alex Drug Discov. Today 9 2004 430
9. Ligand docking was based on a public domain ChK1 structure, PDB entry 1ZYS. Details are provided in Supplemental material.
10. Examples of diarylazine syntheses as represented in Scheme 1: Jenmalm Jensen, A. J.; Ringom, R.; Medina, C.; Shilvock, J.; Wiik, M.; Koolmeister, T.; Angbrant, J.; Henriksson, M.; Sandvall, T.; Sutin, L.; Johansson, L.; Nilsson, B. M. Patent Application US 2008/0039450.
11. Buhr, C. A.; Baik, T.-G.; Ma, S.; Tesfai, Z.; Wang, L.; Co, E. W.; Epshteyn, S.; Kennedy, A. R.; Chen, B.; Dubenko, L.; Anand, N. K.; Tsang, T. H.; Nuss, J. M.; Peto, C. J.; Rice, K. D.; Ibrahim, M. A.; Schnepp, K. L.; Shi, X.; Leahy, J. W.; Chen, J.; Dalrymple, L. E.; Forsyth, T. P.; Huynh, T. P.; Mann, G.; Mann, L. W.; Takeuchi, C. S. U.S. Patent 7,704,995, 2010.
12. For an explanation of 'H2 region' or 'hydrophobic region II': P. Traxler, and P. Furet Pharmacol. Ther. 82 1999 195
13. S. Huang, R.M. Garbaccio, M.E. Fraley, J. Steen, C. Kreatsoulas, G. Hartman, S. Stirdivant, B. Drakas, K. Rickert, E. Walsh, K. Hamilton, C.A. Buser, J. Hardwick, X. Mao, M. Abrams, S. Beck, W. Tao, R. Lobell, L. Sepp-Lorenzino, Y. Yan, M. Ikuta, J. Zugay Murphy, V. Sardana, S. Munshi, L. Kuo, M. Reilly, and E. Mahan Bioorg. Med. Chem. Lett. 16 2006 5907
14. 50 of 6.2 μM and 6.1 μM respectively in the HTS Z-lyte assay.
15. The Cambridge Structural Database (CSD) provides only fused-ring examples incorporating the 2-amino-3-phenylpyrazine moiety, CSD codes: FITZAJ01, GOLDUG, LICZOM, SEWZOJ. F.H. Allen Acta Crystallogr.; Sect. B: Struct. Sci. B58 2002 380
16. Syntheses of compounds 14-16 are detailed in the patent literature: Chen, H.; Dyke, H. J.; Ellwood, C.; Gancia, E.; Gazzard, L. J.; Goodacre, S.; Kintz, S.; Lyssikatos, J.; Macleod, C.; Williams, K. U.S. Patent 8,501,765.
17. R.H. Bahekar, M.R. Jain, P.A. Jadav, A. Goel, D.N. Patel, V.M. Prajapati, A.A. Gupta, H. Modi, and P.R. Patel Bioorg. Med. Chem. 15 2007 5950
18. Synthesis of compound 17 is detailed in the patent literature: Chen, H.; Dyke, H. J.; Gancia, E.; Gazzard, L. J.; Goodacre, S.; Lyssikatos, J.; Macleod, C.; Williams, K. Patent Application US 2011/0124654.
19. P. Chen, C. Luo, Y. Deng, K. Ryan, J. Register, S. Margosiak, A. Tempczyk-Russell, B. Nguyen, P. Myers, K. Lundgren, C.C. Kan, and P.M. O'Connor Cell 100 2000 681
20. Details of the checkpoint abrogation assay are given in Supplemental material. SN-38 is the active metabolite of irinotecan: Y. Kawato, M. Animimi, Y. Hirota, H. Kuga, and K. Sato Cancer Res. 51 1991 4187
21. 10fs is the effective concentration of test compound required for 10-fold sensitization to gemcitabine. Further details of the isobologram assay are given in Supplemental material
22. Selectivity screening was performed by SelectScreen® Kinase Profiling Services (Invitrogen-Life Technologies, Madison, USA) and these data are provided in Supplemental material.