▪ Abstract Tyrosine phosphorylation is one of the key covalent modifications that occurs in multicellular organisms as a result of intercellular communication during embryogenesis and maintenance o...

Protein Tyrosine Kinase Structure and Function

https://www.cell.com/molecular-cell/pdf/S1097-2765(05)00089-4.pdf

Structural Determinants of Phosphoinositide 3-kinase Inhibition by Wortmannin, LY294002, Quercetin, Myricetin, and Staurosporine

Oxyl radicals, redox-sensitive signalling cascades and antioxidants

Y-27632 [(+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide++ + dihydrochloride] is widely used as a specific inhibitor of the Rho-associated coiled-coil forming protein serine/threonine kinase (ROCK) family of protein kinases. This study examined the inhibition mechanism and profile of actions of Y-27632 and a related compound, Y-30141 [(+)-(R)-trans- 4-(1-aminoethyl)-N-(1H-pyrrolo[2, 3-b]pyridin-4-yl)cyclohexan-ecarboxamide dihydrochloride]. 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. This suggests that these compounds inhibit the kinases by binding to the catalytic site. Their affinities for ROCK kinases as determined by K(i) values were at least 20 to 30 times higher than those for two other Rho effector kinases, citron kinase and protein kinase PKN. [(3)H]Y-30141 was taken up by cells in a temperature- and time-dependent and saturable manner, and this uptake was competed with unlabeled Y-27632. No concentrated accumulation was found, suggesting that the uptake is a carrier-mediated facilitated diffusion. Y-27632 abolished stress fibers in Swiss 3T3 cells at 10 microM, but the G(1)-S phase transition of the cell cycle and cytokinesis were little affected at this concentration. Y-30141 was 10 times more potent than Y-27632 in inhibiting the kinase activity and stress fiber formation, and it caused significant delay in the G(1)-S transition and inhibition of cytokinesis at 10 microM.

Pharmacological properties of Y-27632, a specific inhibitor of rho-associated kinases.

Structures of Lung Cancer-Derived Egfr Mutants and Inhibitor Complexes: Mechanism of Activation and Insights Into Differential Inhibitor Sensitivity

Structural analysis of the lymphocyte-specific kinase Lck in complex with non-selective and Src family selective kinase inhibitors

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.

The structure-based design of ATP-site directed protein kinase inhibitors

The Structure-Based Design of ATP-Site Directed Protein Kinase Inhibitors

https://www.cell.com/structure/pdf/S0969-2126(97)00304-3.pdf

Leticia M Toledo

Papers

Structural analysis of the lymphocyte-specific kinase Lck in complex with non-selective and Src family selective kinase inhibitors

The structure-based design of ATP-site directed protein kinase inhibitors

The Structure-Based Design of ATP-Site Directed Protein Kinase Inhibitors

Structures of staurosporine bound to CDK2 and cAPK – new tools for structure-based design of protein kinase inhibitors