Structure-based generation of a new class of potent Cdk4 inhibitors: New de novo design strategy and library design

Journal of Medicinal Chemistry

Volumn 44, Issue 26, 2001, Pages 4615-4627

  Honma, T ^a   Hayashi, K ^a   Aoyama, T ^a   Hashimoto, N ^a   Machida, T ^a   Fukasawa, K ^a   Iwama, T ^a   Ikeura, C ^a   Ikuta, M ^a   Suzuki Takahashi, I ^a   Iwasawa, Y ^a   Hayama, T ^a   Nishimura, S ^a   Morishima, H ^a  

^a TAIHO PHARMACEUTICAL CO LTD   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE TRIPHOSPHATE; ANTINEOPLASTIC AGENT; CYCLIN DEPENDENT KINASE 4; CYCLIN DEPENDENT KINASE INHIBITOR; N (5 OXO 2,3,5,9B TETRAHYDRO 1H PYRROLO[2,1 A]ISOINDOL 9 YL) N' PYRIDIN 2 YLUREA; N (9 OXO 9H FLUOREN 4 YL) N' PYRIDIN 2 YLUREA; PYRIDINE DERIVATIVE; UNCLASSIFIED DRUG; UREA DERIVATIVE;

ARTICLE; CHEMICAL MODIFICATION; DRUG STRUCTURE; IC 50; MOLECULAR MODEL; SEQUENCE HOMOLOGY; STRUCTURE ACTIVITY RELATION; X RAY ANALYSIS;

CDC2-CDC28 KINASES; COMBINATORIAL CHEMISTRY TECHNIQUES; CRYSTALLOGRAPHY, X-RAY; CYCLIN-DEPENDENT KINASE 2; CYCLIN-DEPENDENT KINASE 4; CYCLIN-DEPENDENT KINASES; DRUG DESIGN; ENZYME INHIBITORS; FLUORENES; MAGNETIC RESONANCE SPECTROSCOPY; MODELS, MOLECULAR; PROTEIN BINDING; PROTEIN-SERINE-THREONINE KINASES; PROTO-ONCOGENE PROTEINS; PYRIDINES; STRUCTURE-ACTIVITY RELATIONSHIP; UREA;

EID: 0035924235     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm0103256     Document Type: Article

References (60)

1. Cyclins and cyclin dependent kinases: Take your partners
2. D-type cyclins
3. Cell cycle-dependent phosphorylation of the tumor suppressor RB protein
4. The retinoblastoma protein and a cell cycle control
5. Direct binding of cyclin D to the retinoblastoma gene product (pRB) and pRB phosphorylation by the cyclin D-dependent kinase CDK4
6. Cyclin D1 is nuclear protein required for cell cycle progression in G1
7. Cell-cycle regulators and cancer
8. UCN-01 (7-hydroxystaurosporine) and other indolocarbazole compounds: A new generation of anticancer agents for the new century?
9. Flavopiridol (L86-8275, NSC-649890), a new kinase inhibitor for tumor therapy
10. Phase I trial of continuous infusion flavopiridol, a novel cyclin-dependent kinase inhibitor, in patients with refractory neoplasms
11. Exploiting chemical libraries, structure, and genomics in the search of kinase inhibitors
12. Prido[2,3-d]pyrimidin-7-one inhibitors of cyclin-dependent kinases
13. Indenopyrazoles as novel cyclin dependent kinase (CDK) inhibitors
14. Inhibitors of cyclin dependent kinases as therapeutic agents for the treatment of cancer
15. HIV-1 integrase pharmacophore: Discovery of inhibitors through threedimensional database searching
16. Design, synthesis and X-ray crystallographic studies of novel FKBP-12 ligands
17. Discovering high-affinity ligands for proteins: SAR by NMR
18. Rational design and synthesis of novel, potent bis-phenylamidine carboxylate factor Xa inhibitors
19. Discovery of a new cyclooxygenase-2 lead compound through 3-D database searching and combinatorial chemistry
20. Novel inhibitors of DNA gyrase: 3D structure based biased needle screening, hit validation by biophysical methods, and 3D guided optimization. A promising alternative to random screening
21. Generation and use of threedimensional databases for drug discovery
22. Three-dimensional structure database searches
23. An introduction to de novo ligand design
24. A geometric approach to macromolecule-ligand interactions
25. Automatic creation of drug candidate structures based on receptor structure. Starting point for artificial lead generation
26. Confirmation of usefulness of a structure construction program based on three-dimensional receptor structure for rational lead generation
27. CONCERTS-dynamic connection of fragments as an approach to de novo ligand design
28. PRO-LIGAND: An approach to de novo molecular design. 1. Application to the design of organic molecules
29. The computer program LUDI: A new method for the de novo design of enzyme inhibitors
30. LUDI: Rule-based automatic design of new substituents for enzyme inhibitor leads
31. Crystal structure of cyclin dependent kinase 2
32. Mechanism of CDK activation revealed by the structure of a cyclin A-CDK2 complex
33. Structural basis of cyclin dependent kinase activation by phosphorylation
34. Mechanism of cyclin dependent kinase regulation: Structures of Cdks, their cyclin activators, and cip and ink4 inhibitors
35. Structural basis for inhibition of the cyclin dependent kinase Cdk6 by the tumor suppressor p16INK4a
36. Structural basis of inhibition of CDK-cyclin complexes by INK4 inhibitors
37. Crystal structure of the complex of the cyclin D-dependent kinase Cdk6 bound to the cell-cycle inhibitor p19INK4d
38. The protein kinase family: Conserved features and deduced phylogeny of the catalytic domains
39. Protein kinase catalytic domain sequence database: Identification of conserved features of primary structure and classification of family members
40. Protein kinases. 6. The eukaryotic protein kinase superfamily: Kinase (catalytic) domain structure and classification
41. CHARMM: A program for macromolecular energy, minimization, and dynamic calculation
42. Structural basis for specificity and potency of a flavonoid inhibitor of human CDK2, a cell cycle kinase
43. Protein kinase inhibition by staurosporine revealed in details of the molecular interaction with CDK2
44. Inhibition of cyclin dependent kinases by purine analogs. Crystal structure of human cdk2 complexed with roscovitine
45. Crystal structure of the p27Kipl cyclin dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex
46. Inhibition of cyclin dependent kinases, GSK-3b and CK1 by hymenialdisine, a marine sponge constituent
47. An introduction to de novo ligand design
48. The synthesis of fused ring nitrogen heterocycles via regiospecific intramolecular Heck reactions
49. Crystallographic approach to identification of cyclin dependent kinase 4 (CDK4) specific inhibitors by using CDK4 mimic CDK2 protein
50. A novel approach for the development of selective Cdk4 inhibitors: Library design based on locations of Cdk4 specific amino acid residues
51. Butyrolactone I, a selective inhibitor of cdk2 and cdc2 kinase
52. The consensus motif for phosphorylation by cyclin D1-Cdk4 is different from that for phosphorylation by cyclin A/E-Cdk2