J Chem Inf Model - Insight into the allosteric inhibition of Abl kinase.

Tópicos

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Resumo

Abl kinase inhibitors targeting the ATP binding pocket are currently used as a front-line therapy for the treatment of chronic myelogenous leukemia (CML), but their use has significant limitation because of the development of drug resistance (especially due to the T315I mutation). Two compounds (GNF-2 and BO1) have been found able to inhibit the Abl activity through a peculiar mechanism of action. Particularly, GNF-2 acts as allosteric inhibitor against Bcr-Abl wild type (wt), but it has no activity against the gatekeeper mutant T315I. Its activity against the last mutant reappears when used together with an ATP-competitive inhibitor such as Imatinib or Nilotinib. A crystal structure of GNF-2 bound to the Abl myristoyl pocket (MP) has been released. On the contrary, BO1 shows an ATP-competitive/mixed mechanism of action against the wt, while it acts as an allosteric inhibitor against T315I. In order to better understand the mechanism of Abl allosteric inhibition, MD simulations and MM/GBSA analysis were performed on Abl wt and T315I in complex with GNF-2 and BO1, and the results were compared to those found for the natural myristoyl ligand. Similarly to that observed for the myristoyl group, the binding of an allosteric inhibitor to the MP promotes the formation of a compact and inhibited conformation of the wt protein, characterized by the stabilization of the intramolecular interactions that occur between SH2-SH3 and kinase domains. Conversely, an overall higher flexibility was observed with the Abl T315I mutant, especially in the case of GNF-2. Our analysis highlighted differences in the dynamic behavior of GNF-2 and BO1 which could explain the different biological profiles of the two allosteric inhibitors against the T315I mutant.

Resumo Limpo

abl kinas inhibitor target atp bind pocket current use frontlin therapi treatment chronic myelogen leukemia cml use signific limit develop drug resist especi due ti mutat two compound gnf bo found abl inhibit abl activ peculiar mechan action particular gnf act alloster inhibitor bcrabl wild type wt activ gatekeep mutant ti activ last mutant reappear use togeth atpcompetit inhibitor imatinib nilotinib crystal structur gnf bound abl myristoyl pocket mp releas contrari bo show atpcompetitivemix mechan action wt act alloster inhibitor ti order better understand mechan abl alloster inhibit md simul mmgbsa analysi perform abl wt ti complex gnf bo result compar found natur myristoyl ligand similar observ myristoyl group bind alloster inhibitor mp promot format compact inhibit conform wt protein character stabil intramolecular interact occur shsh kinas domain convers overal higher flexibl observ abl ti mutant especi case gnf analysi highlight differ dynam behavior gnf bo explain differ biolog profil two alloster inhibitor ti mutant

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