Figure 1. Ponatinib avoids the steric hindrance imposed by T315I.

(A) Computer-simulated ribbon depictions of imatinib (purple), nilotinib (orange) and ponatinib (green) bound to BCR-ABL1T^315I mutant. The mutant residue I315 is depicted as red sticks, respectively. Highlights of the interaction of imatinib (B) and ponatinib (C) with the mutant residue I315 of BCR-ABL. Note the difference in steric clash (portrayed as colored areas), accounting for the preserved affinity of ponatinib for the mutant protein with respect to the binding failure of imatinib. (D) Computer simulation of ponatinib bound to the BCR-ABL1T^315I/F317L double mutant. The mutant residues I315 and L317 are depicted as red and yellow sticks, respectively. Drug hydrogen atoms, water molecules and counterions are omitted for clarity. Ponatinib inhibits BCR-ABL1T^315I/F317L with an IC₅₀ of 21nM, 2.8-fold higher than BCR-ABL1T^315I (IC₅₀ 7.4nM).