The document discusses the development of inhibitors for Aurora B kinase, which is overexpressed in many tumors and disrupts mitosis. 3D-QSAR models were developed using molecular field analysis and receptor surface analysis on a set of 27 quinazoline-based Aurora B inhibitors. The models identified specific molecular fields and receptor surface descriptors that correlated with inhibitory activity. The developed QSAR equations can be used to evaluate potential inhibitory activity of new compounds before synthesis and further testing.

1. ANALOGUE BASED DESIGN OF AURORA-B INHIBITORS Dr. Sarma Jagarlapudi Dr. B. Syama Sundar Head of Informatics Dept. of Chemistry GVK Biosciences Acharya Nagarjuna University Hyderabad Guntur Jayashankar. L

5. Mechanism

6. Roles of Aurora Kinases during Mitosis

9. Catalytic active site THE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 277, No. 45, (8), 42419–42422, 2002

10. Aurora Inhibitor VX-680

11. Aurora inhibitors 1) Drugs Fut 2004, 30(1), 2) Bioorg Med Chem Lett. 2006 Mar 1;16(5):1320-3

16. Aurora B inhibitors with observed and calculated biological activities possessing thequinazoline as common scaffold

20. Stereo view of rectangular molecular field surrounding aligned molecules. Some of the field descriptors, which are involved in the QSAR eq 1, are indicated. Correlation of MFA (0.954).

21. Stereo view of the receptor surface which represents the vitural active site. Some of the RSA descriptors that constitute the QSAR eq 2 are labeled. Correlation of RSA (0.949)

22. Statistical Parameters for MFA and RSA

24. References 1. Nicola M. Heron,a, Malcolm Anderson, David P. Blowers et al , “SAR and inhibitor complex structure determination of a novel class of potent and specific Aurora kinase inhibitors”, Bioorg. Med. Chem. Lett. 16 (2006) 1320–1323. 2. J. A. R. P. Sarma, G. Rambabu, K. Srikanth, D. Raveendra and M. Vithal, “Analogue Based Design of MMP-13 (Collagenase-3) Inhibitors”, Bioorg. Med. Chem. Lett. 12 (2002) 2689–2693. 3. Elizabeth A Harrington, David Bebbington, JeffMoore et al, “VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo ”, Nat Med 2004 10(3) 262-267 4. Emilie Montembault, Claude Prigent, “ Aurora kinases:Therapeutic potential”, Drugs of the Future 2005, 30(1) 5. Andrew Mortlock, Nicholas J. Keen, Frederic H. Jung et al., ”Progress in the Development of Selective Inhibitors of Aurora Kinases”, Curr Top Med Chem . 2005;5(2):199-213. 6. Jung FH, Pasquet G, Lambert-van der Brempt C et al., Discovery of novel and potent thiazoloquinazolines as selective Aurora A and B kinase inhibitors” J Med Chem. 2006 Feb 9; 49(3) 955-70