Abstract
BCR-ABL kinase domain inhibition can be used to treat chronic myeloid leukemia. The inhibitors such as imatinib, dasatinib and nilotinib are effective drugs but are resistant to some BCR-ABL mutations. The pan-BCR-ABL kinase inhibitor ponatinib exhibits potent activity against native, T315I, and all other clinically relevant mutants, and showed better inhibition than the previously known inhibitors. We have studied the molecular dynamics simulations and calculated solvated interaction energies of native and fourteen mutant BCR-ABL kinases (M244V, G250E, Q252H, Y253F, Y253H, E255K, E255V, T315A, T315I, F317L, F317V, M351T, F359V and H396P) complexed with ponatinib. These studies revealed that the interactions between ponatinib and individual residues in BCR-ABL kinase are also affected due to the remote residue mutations. We report that some residues, Met244, Lys245, Gln252, Gly254, Leu370 and Leu298 do not undergo any conformational changes, while the fluctuations in residues from P-loop, β3-, β5- strands and αC- helix are mainly responsible for ponatinib binding to native and all mutant BCR-ABL kinases. Our work provides the molecular mechanisms of native and mutant BCR-ABL kinases inhibition by ponatinib at atomic level that has not been studied before.
Highlights
The breakpoint cluster region-Abelson (BCR-ABL) is the cytoplasmic fusion oncoprotein with constitutive tyrosine kinase activity, associated with Philadelphia chromosome responsible for acute lymphoblastic and chronic myeloid leukemias [1,2,3,4]
With the exception of T315I, most BCR-ABL mutations are inhibited by dasatinib and nilotinib
The pan-BCR-ABL kinase inhibitor, ponatinib is most popular for its inhibition of ABLT315I mutation at nano molar concentrations
Summary
The breakpoint cluster region-Abelson (BCR-ABL) is the cytoplasmic fusion oncoprotein with constitutive tyrosine kinase activity, associated with Philadelphia chromosome responsible for acute lymphoblastic and chronic myeloid leukemias [1,2,3,4]. Inhibitors of ABL kinase domain can be used to treat most chronic-phase of CML [11]. Resistance can be traced to the selection of cancer cells with secondary mutations in the targeted kinase. These resistance mutations often appear in the kinase catalytic domain to weaken or prevent interactions with inhibitor [13]. The ABL kinase inhibitor imatinib is effective drug with impressive response and survival rates in the chronic phase of disease [15,16]. Though imatinib is most effective in many cases, mutations in BCR-ABL often lead to resistance. Ponatinib (AP24534), a third generation pan-BCR-ABL kinase inhibitor generated from the structure-guided drug design strategy, is able to inhibit native
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