Antiproliferative agents with anticancer activity continue to be reported in the literature and to progress into clinical development. Active compounds identified in tumor cell-based assays tend to have good solubility and permeability characteristics, thus allowing rapid optimization of properties such as metabolic stability and absorption that are essential to successful drugs. The cell-based screening paradigm does not circumvent some key hurdles in the development of anticancer drugs, such as the poor correlation of in vivo tumor xenograft activity to clinical experience, and the off-target toxicities which are associated with agents that inhibit rapidly proliferating cells . In the absence of a molecular target, the challenge of correlating of xenografts to clinical experience potentially could be overcome by monitoring not just for tumor growth inhibition, but also for biomarkers that predict the onset of apoptosis. In the pre-clinical setting, toxicities are currently predicted by monitoring for weight loss (or death) in treated animals, but the development of the Lilly ASAP series illustrates the use of counter-screening for selectivity vs. normal fibro-blasts. In the final analysis, however, the need for effective anticancer drugs with improved side effect profiles remains, regardless of the initial method of identification of the drugs.
 D. F. Kisor, Ann. Pharmacother., 2005, 39, 1056-1063.
 J. W. Clark, J. P. Eder, D. Ryan, C. Lathia and H.-J. Lenz, Clin. Cancer Res., 2005, 11, 5472-5480.
 A. List, S. Kurtin, D. J. Roe, A. Buresh, D. Mahadevan, D. Fuchs, L. Rimsza, R. Heaton, R. Knight and J. B. Zeldis, New Eng. J. Med., 2005, 352, 549-557.
 Arranon Prescribing Information. October 28, 2005 (cited April 12, 2005), available from: http://www.fda.gov/cder/foi/label/2005/021877lbl.pdf.
 Revlimid Prescribing Information. December 28, 2005 (cited April 12, 2006), available from: http://www.fda.gov/cder/foi/label/2005/021880lbl.pdf.
 A. D. Laird and J. M. Cherrington, Expert Opin. Invest. Drugs, 2003, 12, 51-64.
 B. A. Chabner and T. G. J. Roberts, Nat. Rev.: Cancer, 2005, 5, 65-72.
 K. L. Lobb, P. A. Hipskind, J. A. Aikins, E. Alvarez, Y.-Y. Cheung, E. L. Considine, A. De Dios, G. L. Durst, R. Ferritto, C. S. Grossman, D. D. Giera, B. A. Hollister, Z. Huang, P. W. Iversen, K. L. Law, T. Li, H.-S. Lin, B. Lopez, J. E. Lopez, L. M. Martin Cabrejas, D. J. McCann, V. Molero, J. E. Reilly, M. E. Richett, C. Shih, B. Teicher, J. H. Wikel, W. T. White and M. M. Mader, J. Med. Chem., 2004, 47, 5367-5380.
 M. M. Mader, C. Shih, E. L. Considine, A. De Dios, C. S. Grossman, P. A. Hipskind, H.-S. Lin, K. L. Lobb, B. Lopez, J. E. Lopez, L. M. Martin Cabrejas, M. E. Richett, W. T. White, Y.-Y. Cheung, Z. Huang, J. E. Reilly and S. R. Dinn, Bioorg. Med. Chem. Lett., 2005, 15, 617-620.
 J. N. Weinstein, T. G. Myers, P. M. O'Connor, S. H. Friend, A. J. Fornace, Jr., K. W. Kohn, T. Fojo, S. E. Bates, L. V. Rubinstein, N. L. Anderson, J. K. Buolamwini, W. W. Van Osdol, A. P. Monks, D. A. Scudiero, E. A. Sausville, D. W. Zaharevitz, B. Bunow, V. N. Viswanadhan, G. S. Johnson, R. E. Wittes and K. D. Paull, Science, 1997, 275, 343-349.
 C. A. Lipinski, F. Lombardo, B. W. Dominy and P. J. Feeney, Adv. Drug Delivery Rev., 1997, 23, 3-25.
 G. Simon, M. Sovak, M. Wagner, E. Haura, S. Gerst, D. deAlwis, G. Bepler, D. Sullivan, A. Weitzman and D. Spriggs, Eur. J. Cancer (Supplements), 2004, 2, 69, abs. 228.
 K. Tomita, Y. Tsuzuki, K.-i. Shibamori, M. Tashima, F. Kajikawa, Y. Sato, S. Kashimoto, K. Chiba and K. Hino, J. Med. Chem., 2002, 45, 5564-5575.
 Y. Tsuzuki, K. Tomita, K. Shibamori, Y. Sato, S. Kashimoto and K. Chiba, J. Med. Chem., 2004, 47, 2097-2109.
 W. E. Kohlbrenner, N. Wideburg, D. Weigl, A. Saldivar and D. T. Chu, Antimicrob. Agents Chemotherap., 1992, 36, 81-86.
 M. J. Robinson, B. A. Martin, T. D. Gootz, P. R. McGuirk and N. Osheroff, Antimicrob. Agents Chemotherap., 1992, 36, 751-756.
 M. P. Wentland, G. Y. Lesher, M. Reuman, M. D. Gruett, B. Singh, S. C. Aldous, P. H. Dorff, J. B. Rake and S. A. Coughlin, J. Med. Chem., 1993, 36, 2801-2809.
 J. Hyde, J. Wright, D. H. Walker, J. A. Silverman and M. R. Arkin, Proc. Am. Assoc. Cancer Res., 2006, 47, abs. 2074.
 S. Ebbinghaus, M. Gordon, R. Advani, H. Hurwitz, D. Mendelson, H. Wakelee, U. Hoch, J. A. Silverman, N. Havrilla and D. Adelman, Proc. Am. Assoc. Cancer Res., 2006, 47, abs. 2913.
 C. G. Mortimer, G. Wells, J.-P. Crochard, E. L. Stone, T. D. Bradshaw, M. F. G. Stevens and A. D. Westwell, J. Med. Chem., 2006, 49, 179-185.
 M. R. Boyd and K. D. Paull, Drug Devel. Res., 1995, 34, 91-109.
 C. Congiu, M. T. Cocco, V. Lilliu and V. Onnis, J. Med. Chem., 2005, 48, 8245-8252.
 T. Akama, Y. Shida, T. Sugaya, H. Ishida, K. Gomi and M. Kasai, J. Med. Chem., 1996, 39, 3461-3469.
 T. Akama, H. Ishida, Y. Shida, U. Kimura, K. Gomi, H. Saito, E. Fuse, S. Kobayashi, N. Yoda and M. Kasai, J. Med. Chem., 1997, 40, 1894-1900.
 T. Akama, H. Ishida, U. Kimura, K. Gomi and H. Saito, J. Med. Chem., 1998, 41, 2056-2067.
 M. J. Kuffel, J. C. Schroeder, L. J. Pobst, S. Naylor, J. M. Reid, S. H. Kaufmann and M. M. Ames, Mol. Pharmacol., 2002, 62, 143-153.
 A. I. Loaiza-Perez, S. Kenney, J. Boswell, M. Hollingshead, M. C. Alley, C. Hose, H. P. Ciolino, G. C. Yeh, J. B. Trepel, D. T. Vistica and E. A. Sausville, Mol. Cancer Therap., 2004, 3, 715-725.
 L.-h. Meng, G. Kohlhagen, Z.-y. Liao, S. Antony, E. Sausville and Y. Pommier, Cancer Res., 2005, 65, 5337-5343.
 A. Link and C. Kunick, J. Med. Chem., 1998, 41, 1299-1305.
 C. Kunick, C. Bleeker, C. Pruehs, F. Totzke, C. Schaechtele, M. H. G. Kubbutat and
A. Link, Bioorg. Med. Chem. Lett., 2006, 16, 2148-2153.
 M. G. Ferlin, G. Chiarelotto, V. Gasparotto, L. Dalla Via, V. Pezzi, L. Barzon, G. Palu and I. Castagliuolo, J. Med. Chem., 2005, 48, 3417-3427.
 V. Gasparotto, I. Castagliuolo, G. Chiarelotto, V. Pezzi, D. Montanaro, P. Brun, G. Palu, G. Viola and M. G. Ferlin, J. Med. Chem., 2006, 49, 1910-1915.
 W. Kemnitzer, J. Drewe, S. Jiang, H. Zhang, Y. Wang, J. Zhao, S. Jia, J. Herich, D. Labreque, R. Storer, K. Meerovitch, D. Bouffard, R. Rej, R. Denis, C. Blais, S. Lamothe, G. Attardo, H. Gourdeau, B. Tseng, S. Kasibhatla and S. X. Cai, J. Med. Chem., 2004, 47, 6299-6310.
 S. Kasibhatla, H. Gourdeau, K. Meerovitch, J. Drewe, S. Reddy, L. Qiu, H. Zhang, F. Bergeron, D. Bouffard, Q. Yang, J. Herich, S. Lamothe, S. X. Cai and B. Tseng, Mol. Cancer Therap., 2004, 3, 1365-1374.
 H. Gourdeau, L. Leblond, B. Hamelin, C. Desputeau, K. Dong, I. Kianicka, D. Cust-eau, C. Boudreau, L. Geerts, S.-X. Cai, J. Drewe, D. Labrecque, S. Kasibhatla and
 T. Nemoto, T. Ohshima and M. Shibasaki, Tetrahedron, 2003, 59, 6889-6897.
 S. Lee, Y. S. Lee, S. H. Jung, K. H. Shin, B.-K. Kim and S. S. Kang, Arch. Pharm. Res., 2003, 26, 727-730.
 D. Yim, R. P. Singh, C. Agarwal, S. Lee, H. Chi and R. Agarwal, Cancer Res., 2005, 65, 1035-1044.
 A. Kamb, Nat. Rev. Drug Discov., 2005, 4, 161-164.
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