Journal ArticleDOI
The Structure-Based Design of ATP-Site Directed Protein Kinase Inhibitors
TLDR
The structure basis for selectivity and potency has now been clarified with the crystallization of a number of such targets in complex with inhibitors and the structure based exploitation of additional highly validated targets from a variety of therapeutic areas is now ripe.Abstract:
The protein kinase family represents both a huge opportunity and a challenge for drug development. The conservation of structural features within the ATP binding cleft initially led to the belief that specificity would be difficult to achieve. This dogma has now been clearly dispelled with the discovery and clinical testing of a group of first generation compounds, which are characterized by a high degree of selectivity towards a variety of oncology targets. The structural basis for selectivity and potency has now been clarified with the crystallization of a number of such targets in complex with inhibitors. The protein kinase inhibitor field is now ripe for the structure based exploitation of additional highly validated targets from a variety of therapeutic areas.read more
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Structural Determinants of Phosphoinositide 3-kinase Inhibition by Wortmannin, LY294002, Quercetin, Myricetin, and Staurosporine
Edward H. Walker,Michael E. Pacold,Olga Perisic,Len R. Stephens,Philip T. Hawkins,Matthias P. Wymann,Roger L. Williams +6 more
TL;DR: Interestingly, LY294002 and the lead compound on which it was designed, quercetin, as well as the closely related flavonoid myricetin bind PI3K in remarkably different orientations that are related to each other by 180 degrees rotations.
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Pharmacological properties of Y-27632, a specific inhibitor of rho-associated kinases.
Toshimasa Ishizaki,Masayoshi Uehata,Ichiro Tamechika,Jeongsin Keel,Kimiko Nonomura,Midori Maekawa,Shuh Narumiya +6 more
TL;DR: Y-27632 and Y-30141 inhibited the kinase activity of both ROCK-I and ROCK-II in vitro, and this inhibition was reversed by ATP in a competitive manner, suggesting that these compounds inhibit the kinases by binding to the catalytic site.
Journal ArticleDOI
Lessons learned from the development of an Abl tyrosine kinase inhibitor for chronic myelogenous leukemia
TL;DR: The experience in the preclinical and clinical development of a Bcr-Abl inhibitor as a therapeutic agent for chronic myelogenous leukemia (CML) is discussed, and how this experience and other recent advances in the field could contribute to drug development for other diseases are considered.
Journal ArticleDOI
Flavopiridol inactivates P-TEFb and blocks most RNA polymerase II transcription in vivo.
Sheng-Hao Chao,David H. Price +1 more
TL;DR: It is concluded that P-TEFb is required for transcription of most RNA polymerase II molecules in vivo using nuclear run-on assays and the apparent lack of competition with ATP could be caused by a very tight binding of the drug.
Journal ArticleDOI
Classification of kinase inhibitors using a Bayesian model.
TL;DR: The use of Bayesian statistics to model both general (multifamily) and specific (single-target) kinase inhibitors is investigated, demonstrating an alternative to current computational methods applied to heterogeneous structure/activity data sets.
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Journal Article
The structure-based design of ATP-site directed protein kinase inhibitors
TL;DR: The protein kinase inhibitor field is now ripe for the structure based exploitation of additional highly validated targets from a variety of therapeutic areas as mentioned in this paper, and the structural basis for selectivity and potency has now been clarified with the crystallization of a number of such targets in complex with inhibitors.