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Identification of Novel p38α MAP Kinase Inhibitors Using Fragment-Based Lead Generation
Open accessAbstract
We describe the structure-guided optimization of the molecular fragments 2-amino-3-benzyloxypyridine 1 (IC(50) 1.3 mM) and 3-(2-(4-pyridyl)ethyl)indole 2 (IC(50) 35 microM) identified using X-ray crystallographic screening of p38alpha MAP kinase. Using two separate case studies, the article focuses on the key compounds synthesized, the structure-activity relationships and the binding mode observations made during this optimization process, resulting in two potent lead series that demonstrate significant increases in activity. We describe the process of compound elaboration either through the growing out from fragments into adjacent pockets or through the conjoining of overlapping fragments and demonstrate that we have exploited the mobile conserved activation loop, consisting in part of Asp168-Phe169-Gly170 (DFG), to generate significant improvements in potency and kinase selectivity.
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Cited by
Fragment-Based Lead Discovery Using X-ray Crystallography
Hartshorn, M. J., Murray, C. W., Cleasby, A., Frederickson, M., Tickle, I. J., & Jhoti, H. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm0495778 · Cited by 422
Self-citationKeynote review: Structural biology and drug discovery
Congreve, M., Murray, C. W., & Blundell, T. L. (2005) · Drug Discovery Today · doi:10.1016/s1359-6446(05)03484-7 · Cited by 338
Self-citationKLIFS: A Knowledge-Based Structural Database To Navigate Kinase–Ligand Interaction Space
van Linden, O. P. J., Kooistra, A. J., Leurs, R., de Esch, I. J. P., & de Graaf, C. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm400378w · Cited by 298
Hit discovery and hit-to-lead approaches
Keserű, G. M., & Makara, G. M. (2006) · Drug Discovery Today · doi:10.1016/j.drudis.2006.06.016 · Cited by 256
Smith, A. J. T., Zhang, X., Leach, A. G., & Houk, K. N. (2009) · Journal of Medicinal Chemistry · doi:10.1021/jm800498e · Cited by 193
Metadata
- Authors
- Gill, A. L., Frederickson, M., Cleasby, A., Woodhead, S. J., Carr, M. G., Woodhead, A. J., Walker, M. T., Congreve, M. S., Devine, L. A., Tisi, D., O'Reilly, M., Seavers, L. C. A., Davis, D. J., Curry, J., Anthony, R., Padova, A., Murray, C. W., Carr, R. A. E., & Jhoti, H.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2004-12-21
- Volume
- 48
- Issue
- 2
- Pages
- 414-426
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2117643210
- Cited by
- 186
- References
- 0
- FWCI
- 14.29
- Type
- journal article
- Language
- en
- Open access
- green
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- The paper
- Gill, A. L., Frederickson, M., Cleasby, A., Woodhead, S. J., Carr, M. G., Woodhead, A. J., Walker, M. T., Congreve, M. S., Devine, L. A., Tisi, D., O'Reilly, M., Seavers, L. C. A., Davis, D. J., Curry, J., Anthony, R., Padova, A., Murray, C. W., Carr, R. A. E., & Jhoti, H. (2005). Identification of Novel p38α MAP Kinase Inhibitors Using Fragment-Based Lead Generation. Journal of Medicinal Chemistry. https://doi.org/10.1021/jm049575n
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