Tyrosine kinase inhibition: Ligand binding and conformational change in c‐Kit and c‐Abl

Abstract

a b s t r a c tThe conformational flexibility exhibited by protein kinases poses an enormous challenge to the design of cancer therapeutics. Additionally the high degree of structural conservation within the kinase superfamily often leads to inhibitors that exhibit little selectivity and substantial cross reactivity. This work investigates the conformational changes that accompany the binding of Gleevec, or imatinib mesylate, to the tyrosine kinases c-Kit and c-Abl. Our analysis is that this fit is driven, at least in part, by the need to exclude water from solvent-exposed backbone hydrogen bonds. Both experimental and molecular modeling studies of the active state inhibitor of the tyrosine kinase c-Abl indicate that solvent exclusion also plays a role in this system.

A model for non-obligate oligomer formation in protein aggregration

“…Clues as to what form these non-native oligomers might take are available from the biological assembly predicted for the G85R SOD1 mutant. As we have previously demonstrated [24,25,32] exposure of a region, such as the short helix patched by Trp 32 in the tetramer from Fig. 1, to solvent would lead to a loss of secondary structure.…”

“…Solvent-exposed intramolecular backbone hydrogen bonds, or dehydrons, have been previously identified as vulnerabilities or structural defects, in the packing of a wide array of proteins [23,24]. Exposure of such dehydrons to an aqueous environment has been shown to weaken protein secondary structures [25,26].…”

Acetylenic inhibitors of ADAM10 and ADAM17: In silico analysis of potency and selectivity

“…This greater movement undoubtedly co-relates with less efficient binding, and explains the larger IC 50 values observed experimentally. That conformational change leading to solvent exclusion can lead to more effective hydrogen bonding, and thus more effective ligand binding, has been previously proposed by us [20] and others [21]. This inherent flexibility in the unstructured loop spanning Tyr 436 to His 444 is evidenced by differing values of 4.5Å and 4.9Å for the distance between the sulfonyl oxygen and the Ala 439 nitrogen observed for the two subunits of PDB entry 1BKC.…”

Tumor-Stammzellforschung – Basis und Herausforderung für Diagnostik und Therapie

“…Wichtige Beispiele dafür sind HER-2/neu (90), AXL [99] das mutierte Ras [46], das mutierte KIT [100] oder BCR/ABL [100,101], die mit spezifi schen Agentien und neuen Tyrosinkinase-Inhibitoren erreicht werden können. Unerwarteter Weise führt die Behandlung der BCR/ABL+ CML mit Imatinib nicht unbedingt zu einer kompletten Eliminierung des leukämischen Klons, was als Hinweis auf entsprechende Resistenzmechanismen in den Stammzellen gedeutet wird [14].…”