3530
D. M. Burns et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3525–3530
M.; Zhuo, J.; Li, Y.-L.; Lin, Q.; Burns, D.; Xu, M.; Zhang, C.; Qian, D.-Q.; He, C.;
Sharief, V.; Weng, L.; Agrios, C.; Shi, E.; Metcalf, B.; Newton, R.; Friedman, S.;
Yao, W.; Scherle, P.; Hollis, G.; Burn, T. C. Cancer Biol. Ther. 2006, 5, 657.
6. Yao, W.; Zhou, J.; Burns, D. M.; Xu, M.; Zhang, C.; Li, Y.-L.; Qian, D.-Q.; He, C.;
Weng, L.; Shi, E.; Lin, Q.; Agrios, C.; Burn, T. C.; Caulder, E.; Covington, M. B.;
Fridman, J. S.; Friedman, S.; Katiyar, K.; Hollis, G.; Li, Y.; Liu, C.; Liu, X.; Marando,
C. A.; Newton, R.; Pan, M.; Scherle, P.; Taylor, N.; Vaddi, K.; Wasserman, Z. R.;
Wynn, R.; Yeleswaram, S.; Jalluri, R.; Bower, M.; Zhou, B.-B.; Metcalf, B. J. Med.
Chem. 2007, 50, 603.
7. Cellular assay for HER-2 shedding: BT474 cells, a human breast cell cancer
line that constitutively sheds HER-2, were incubated with compound for
72 h at 37 °C, 5% CO2. Supernatants were tested for inhibition of HER-2
sheddase by commercial ELISA. Compound inhibition was determined
relative to cells cultured alone and compound activity was reported as the
inhibitor concentration required for 50% inhibition (IC50 values) of HER-2
sheddase. Internal standards INCB46 and INCB4601 were used to determine
the standard deviations. The average IC50 values are expressed in nM with
the corresponding standard deviation and number of experiments performed
(n) to determine these values. INCB46: 48 20 (n = 105); INCB4601: 106 43
(n = 13).
catalyzed reduction is the less active HER-2 sheddase inhibitor,
which has led to an ongoing investigation to prepare the active iso-
mer stereoselectively.
In summary we have demonstrated that perturbation of the P1
substituent may be a useful tool to modify the metalloprotease
binding profile of a HER-2 sheddase inhibitor and may serve to
augment the influence of conventional P10 permutations, particu-
larly when P10 modifications have reached a plateau. The apparent
divergence between HER-2 sheddase and MMP-2 within the S1
pocket and/or surrounding cleft is of particular utility, since there
is a high level of homology within the S10 subsite and achieving
MMP selectivity via P10 alterations can prove to be an arduous task.
The encouraging results presented thus far prompted a compre-
hensive study of the SAR with regards to the P1 group and the re-
sults of this study are impending.
8. ADAM-10: Rosendahl, M. S.; Ko, S. C.; Long, D. L.; Brewer, M. T.; Rosenzweig, B.;
Hedl, E.; Anderson, L.; Pyle, S. M.; Moreland, J.; Meyers, M. A.; Kohno, T.; Lyons,
D.; Lichenstein, H. S. J. Biol. Chem. 1997, 272, 24588; MMP-1: Templeton, N. S.;
Brown, P. D.; Levy, A. T.; Margulies, I. M. K.; Liotta, L. A.; Stetler-Stevenson, W.
G. Cancer Res. 1990, 50, 5431; MMP-2 and MMP-9: Chandler, S.; Coates, R.;
Gearing, A.; Lury, J.; Wells, G.; Bone, E. Neurosci. Lett. 1995, 201, 223; MMP-3:
Saus, J.; Quinones, S.; Otani, Y.; Nagase, H.; Harris, E. D., Jr.; Kurkinen, M. J. Biol.
Chem. 1988, 263, 6742. An internal standard INCB4601 was used in the
enzymatic assays to determine the standard deviations. The average IC50 values
are expressed in nM with the corresponding standard deviation and number of
experiments performed (n) to determine these values. ADAM-10: 115 32
(n = 69); MMP-2: 781 293 (n = 60).
Acknowledgments
The authors would like to thank Mei Li, Laurine Galya, Jin Liu,
and Karl Blom of the analytical group, Gengjie Yang and Xiangdong
Liu from the drug discovery biology group, and Qiyan Lin of the
medicinal chemistry group for their assistance in conducting the
necessary experiments and providing helpful discussions.
References and notes
9. (a) Condon, J. S.; Joseph-McCarthy, D.; Levin, J. I.; Lombart, H.-G.; Lovering, F. E.;
Sun, L.; Wang, W.; Xu, W.; Zhang, Y. Bioorg. Med. Chem. Lett. 2007, 17, 34; (b)
Park, K.; Aplasca, A.; Du, M. T.; Sun, L.; Zhu, Y.; Zhang, Y.; Levin, J. I. Bioorg. Med.
Chem. Lett. 2006, 16, 3927.
1. (a) Jarvis, L. M. Chem. Eng. News 2006, 84, 21; (b) Engel, R. H.; Kaklamani, V. G.
Drugs 2007, 67, 1329; (c) Bartsch, R.; Wenzel, C.; Zielinski, C. C.; Steger, G. G.
Bio. Drugs 2007, 21, 69; (d) Ross, J. S.; Schenkein, D. P.; Pietrusko, R.; Rolfe, M.;
Linette, G. P.; Stec, J.; Stagliano, N. E.; Ginsburg, G. S.; Symmans, W. F.; Pusztai,
L.; Hortobagyi, G. N. Am. J. Clin. Pathol. 2004, 122, 598.
2. (a) Nahta, R.; Esteva, F. J. Cancer Lett. 2006, 232, 123; (b) Plosker, G. L.; Keam, S.
J. Drugs 2006, 66, 449; (c) Kamath, S.; Buolamwini, J. K. Med. Res. Rev. 2006, 26,
569; (d) Johnston, J. B.; Navaratnam, S.; Pitz, M. W.; Maniate, J. M.; Wiechec, E.;
Baust, H.; Gingerich, J.; Skliris, G. P.; Murphy, L. C.; Los, M. Curr. Med. Chem.
2006, 13, 3483.
3. (a) Muller, A. J.; Scherle, P. A. Nat. Rev. 2006, 6, 613; (b) Spector, N.; Xia, W.; El-
Hariry, I.; Yarden, Y.; Bacus, S. Breast Cancer Res. 2007, 9, 205; (c) Jackisch, C.
Oncologist 2006, 11, 34; (d) Baselga, J.; Arteaga, C. L. J. Clin. Onc. 2005, 23, 2445.
4. (a) Fridman, J. S.; Caulder, E.; Hansbury, M.; Liu, X.; Yang, G.; Wang, Q.; Lo, Y.;
Zhou, B.-B.; Pan, M.; Thomas, S. M.; Grandis, J. R.; Zhou, J.; Yao, W.; Newton, R.
C.; Friedman, S. M.; Scherle, P. A.; Vaddi, K. Clin. Cancer Res. 2007, 13, 1892; (b)
Zhou, B.-B. S.; Peyton, M.; He, B.; Liu, C.; Girard, L.; Caudler, E.; Lo, Y.; Baribaud,
F.; Mikami, I.; Reguart, N.; Yang, G.; Li, Y.; Yao, W.; Vaddi, K.; Gazdar, A. F.;
Friedman, S. M.; Jablons, D. M.; Newton, R. C.; Fridman, J. S.; Minna, J. D.;
Scherle, P. A. Cancer Cell 2006, 10, 39; (c) Liu, X.; Fridman, J. S.; Wang, Q.;
Caulder, E.; Yang, G.; Covington, M.; Liu, C.; Marando, C.; Zhou, J.; Li, Y.; Yao, W.;
Vaddi, K.; Newton, R. C.; Scherle, P. A.; Friedman, S. M. Cancer Biol. Ther. 2006, 5,
648.
10. (a) Levin, J. I.; Chen, J.; Du, M.; Hogan, M.; Kincaid, S.; Nelson, F. C.; Venkatesan,
A. M.; Wehr, T.; Zask, A.; DiJoseph, J.; Killar, L. M.; Skala, S.; Sung, A.; Sharr, M.;
Roth, C.; Jin, G.; Cowling, R.; Mohler, K. M.; Black, R. A.; March, C. J.; Skotnicki, J.
S. Bioorg. Chem. Lett. 2001, 11, 2189; (b) Hanessian, S.; Bouzbouz, S.; Boudon,
A.; Tucker, G. C.; Peyroulan, D. Bioorg. Chem. Lett. 1999, 9, 1691; (c) Curtin, M.
L.; Garland, R. B.; Davidsen, S. K.; Marcotte, P. A.; Albert, D. H.; Magoc, T. J.;
Hutchins, C. Biorg. Med. Chem. Lett. 1998, 8, 1443; (d) Chapman, K. T.; Wales, J.;
Sahoo, S. P.; Niedzwiecki, L. M.; Izquierdo-Martin, M.; Chang, B. C.; Harrison, R.
K.; Stein, R. L.; Hagmann, W. K. Bioorg. Med. Chem. Lett. 1996, 6, 329.
11. Excellent reviews: (a) Babine, R. E.; Bender, S. L. Chem. Rev. 1997, 97, 1359; (b)
Brown, S.; Meroueh, S. O.; Fridman, R.; Mobashery, S. Curr. Top. Med. Chem.
2004, 4, 1227; (c) Levin, J. I. Curr. Top. Med. Chem. 2004, 4, 1289; (d) Skiles, J. W.;
Gonnella, N. C.; Jeng, A. Y. Curr. Med. Chem. 2004, 11, 2911.
12. (a) Fisher, J. F.; Mobashery, S. Cancer Met. Rev. 2006, 25, 115; (b) Bachmeier, B.
E.; Iancu, C. M.; Jochum, M.; Nerlich, A. G. Exp. Rev. Anticancer Ther. 2005, 5,
149; (c) Coussens, L. M.; Fingleton, B.; Matrisian, L. M. Science 2002, 295, 2387.
13. Yao, W.; Zhuo, J.; Burns, D. M.; Li, Y.-L.; Qian, D.-Q.; Zhang, C.; He, C.; Xu, M.;
Shi, E.; Li, Y.; Marando, C. A.; Covington, M. B.; Yang, G.; Liu, X.; Pan, M.;
Fridman, J. S.; Scherle, P.; Friedman, S.; Metcalf, B. Bioorg. Med. Chem. Lett. 2008,
18, 159.
14. Sousa, H. A.; Crespo, J. G.; Afonso, C. A. M. Tetrahedron: Asymmetry 2000, 11,
929.
5. Liu, P. C. C.; Liu, X.; Li, Y.; Covington, M.; Wynn, R.; Huber, R.; Hillman, M.; Yang,
G.; Ellis, D.; Marando, C.; Katiyar, K.; Bradley, J.; Abremski, K.; Stow, M.; Rupar,