Entry into a new class of protein kinase inhibitors by pseudo ring design

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 3, 2008, Pages 897-900

  Furet, Pascal ^a   Caravatti, Giorgio ^a   Guagnano, Vito ^a   Lang, Marc ^a   Meyer, Thomas ^a   Schoepfer, Joseph ^a  

^a NOVARTIS PHARMA AG   (Switzerland)

Author keywords

Kinase; Pseudo ring; Scaffold morphing

Indexed keywords

HYDROGEN; PD 166285; PROTEIN KINASE; PROTEIN KINASE INHIBITOR; PYRIDO(2,3 DEXTRO)PYRIMIDIN 7 ONE; PYRIMIDIN 4 YLUREA; UNCLASSIFIED DRUG; UREA DERIVATIVE;

ARTICLE; DRUG DESIGN; DRUG INHIBITION; DRUG STRUCTURE; HYDROGEN BOND; PROTEIN MOTIF;

AMINO ACIDS; DRUG DESIGN; MODELS, MOLECULAR; MOLECULAR CONFORMATION; MOLECULAR MIMICRY; MOLECULAR STRUCTURE; PROTEIN KINASE INHIBITORS; PYRIDONES; PYRIMIDINES; STRUCTURE-ACTIVITY RELATIONSHIP; UREA;

EID: 38749129660     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.12.041     Document Type: Article

References (20)

1. Bilton C., Allen F.H., Shields G.P., and Howard J.A.K. Acta Crystallogr. B B56 (2000) 849
2. Furet P., Bold G., Hofmann F., Manley P., Meyer T., and Altmann K.H. Bioorg. Med. Chem. Lett. 13 (2003) 2967
3. Liechti C., Séquin U., Bold G., Furet P., Meyer T., and Traxler P. Eur. J. Med. Chem. 39 (2004) 11
4. Klutchko S.R., Hamby J.M., Boschelli D.H., Wu Z., Kraker A.J., Amar A.M., Hartl B.G., Shen C., Klohs W.D., Steinkampf R.W., Driscoll D.L., Nelson J.M., Elliott W.L., Roberts B.J., Stoner C.L., Vincent P.W., Dykes D.J., Panek R.L., Lu G.H., Major T.C., Dahring T.K., Hallak H., Bradford L.A., Showalter H.D.H., and Doherty A.M. J. Med. Chem. 41 (1998) 3276
5. VanderWel S.N., Harvey P.J., McNamara D.J., Repine J.T., Keller P.R., Quin III J., Booth R.J., Elliott W.L., Dobrusin E.M., Fry D.W., and Toogood P.L. J. Med. Chem. 48 (2005) 2371
6. Panek R.L., Lu G.H., Klutchko S.R., Batley B.L., Dahring T.K., Hamby J.M., Hallak H., Doherty A.M., and Keiser J.A. J. Pharmacol. Exp. Ther. 283 (1997) 1433
7. For recent examples, see. Cao J., Fine R., Gritzen C., Hood J., Kang X., Klebansky B., Lohse D., Mak C.C., McPherson A., Noronha G., Palanki M.S.S., Pathak V.P., Renick J., Soll R., Zeng B., and Zhu H. Bioorg. Med. Chem. Lett. 17 (2007) 5812
8. McDermott L.A., Simcox M., Higgins B., Nevins T., Kolinsky K., Smith M., Yang H., Li J.K., Chen Y., Ke J., Mallalieu N., Egan T., Kolis S., Railkar A., Gerber L., and Luk K.-C. Bioorg. Med. Chem. Lett. 13 (2005) 4835
9. Sabat M., VanRens J.C., Brugel T.A., Maier J., Laufersweiler M.J., Golebiowski A., De B., Easwaran V., Hsieh L.C., Rosegen J., Berberich S., Suchanek E., and Janusz M.J. Bioorg. Med. Chem. Lett. 16 (2006) 4257
10. These structures have the following entry codes in the Cambridge Structural Database: BPCTHA, CNBPCT, KPRCGM20, PCMTRE10, PCTRIB10, PUCGLR10, and PURTRE.
11. ** basis set and doing full geometry optimization. A preliminary systematic conformational analysis of the model compound by molecular mechanics varying all torsion angles identified the extended and pseudo cyclic conformations A and B as the low energy conformations of this system. In the subsequent quantum mechanical calculations, B was computed to be more stable than A: by 3.2 kcal/mol in the gas phase and by 0.5 kcal/mol applying the water solvation model available in Jaguar.
12. The protein kinase inhibition assays used in this study are described in the following references. Garcia-Echeverria C., Pearson M.A., Marti A., Meyer T., Mestan J., Zimmermann J., Gao J., Brueggen J., Capraro H.-G., Cozens R., Evans D.B., Fabbro D., Furet P., Porta D.G., Liebetanz J., Martiny-Baron G., Ruetz S., and Hofmann F. Cancer Cell 5 (2004) 231
13. Furet P., Bold G., Meyer T., Roesel J., and Guagnano V. J. Med. Chem. 49 (2006) 4451
14. Nagar B., Bornmann W.G., Pellicena P., Schindler T., Veach D.R., Miller W.T., Clarkson B., and Kuriyan J. Cancer Res. 62 (2002) 4236
15. Compound 1 was docked in the crystal structure of the kinase domain of c-Abl in complex with a pyrido[2,3-d]pyrimidin-7-one inhibitor (PD 173955) published in reference 11 (PDB entry code 1M52). Compound 1 was aligned on PD 173955 in the ATP pocket according to our mimetism concept. Then, PD 173955 was removed and the resulting complex energy minimized in Macromodel using the AMBER/H2O/GBSA force field. Macromodel. Mohamadi F., Richards N.G.J., Guida W.C., Liskamp R., Lipton M., Caufield C., Chang G., Hendrickson T., and Still W.C. J. Comput. Chem. 11 (1990) 440
16. The gate keeper is the main residue determining the selectivity of ATP site directed kinase inhibitors. Named like this because it controls the access to the hydrophobic back pocket of the ATP binding site, it is located at the beginning of the hinge segment, the amino acid stretch that connects the N- and C-terminal domains of a kinase. In c-Abl, this residue is Thr315. For recent papers discussing the role of the gate keeper residue in determining kinase inhibitor selectivity, see for instance. Furet P., Bold G., Meyer T., Roesel J., and Guagnano V. J. Med. Chem. 49 (2006) 4451
17. Vieth M., Higgs R.E., Robertson D.H., Shapiro M., Gragg E.A., and Hemmerle H. Biochim. Biophys. Acta., Proteins Proteomics 1697 (2004) 243
18. 16
19. Ding, Q.; Gary, N. S.; Li, B.; Liu, Y.; Sim, T.; Uno, T.; Zhang, G.; Pissot Soldermann, C.; Breitenstein, W.; Bold, G.; Caravatti, G.; Furet, P.; Guagnano, V.; Lang, M.; Manley, P. W.; Schoepfer, J.; Spanka, C. WO 2006/000420. Chem. Abstr. 2006, 144, 108347.
20. Maier J.A., Brugel T.A., Sabat M., Golebiowski A., Laufersweiler M.J., VanRens J.C., Hopkins C.R., De B., Hsieh L.C., Brown K.K., Easwaran V., and Janusz M.J. Bioorg. Med. Chem. Lett. 16 (2006) 3646