Molecular modeling of FLT3 inhibitors

All three compounds have been previously co-crystallized with other class III receptor tyrosine kinases (PLX3397 in CSF1R, sorfenib in KDR, and ponatinib in KIT). Given the high degree of homology between these kinases and FLT3, we expect these inhibitors will exhibit the same overall binding modes. For each inhibitor, we performed structural alignment between the known co-structure containing the inhibitor and the co-structure of FLT3-quizartinib with an emphasis on optimal registration of ATP-binding apparatus. The pose of the inhibitor was then “copied” from its co-structure with another kinase and “pasted” into FLT3 to replace quizartinib. One round of energy minimization using the default parameter of MOE (Chemical Computing Group, Montreal, Quebec, Canada H3A 2R7) was used to refine the structural model.

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Smith C.C., Zhang C., Lin K., Lasater E.A., Zhang Y., Massi E., Damon L.E., Pendleton M., Bashir A., Sebra R., Perl A., Kasarskis A., Shellooe R., Tsang G., Carias H., Powell B., Burton E.A., Matusow B., Zhang J., Spevak W., Ibrahim P.N., Le M.H., Hsu H.H., Habets G., West B.L., Bollag G, & Shah N.P. (2015). Characterizing and Overriding the Structural Mechanism of the Quizartinib-resistant FLT3 “Gatekeeper” F691L Mutation with PLX3397. Cancer discovery, 5(6), 668-679.

Publication 2015

Csf1r Flt3 Inhibitors Kinase Plx3397 Ponatinib Quizartinib Receptor tyrosine kinases

Corresponding Organization : University of California, San Francisco

Other organizations : Icahn School of Medicine at Mount Sinai, University of Pennsylvania

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Variable analysis

independent variables

PLX3397 in CSF1R
Sorfenib in KDR
Ponatinib in KIT

dependent variables

Binding modes of the inhibitors in FLT3

control variables

Structural alignment between the known co-structure containing the inhibitor and the co-structure of FLT3-quizartinib with an emphasis on optimal registration of ATP-binding apparatus
One round of energy minimization using the default parameter of MOE (Chemical Computing Group, Montreal, Quebec, Canada H3A 2R7) to refine the structural model

positive controls

Co-structure of FLT3-quizartinib

negative controls

Not mentioned

Annotations

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