Structure of the ABL2/ARG kinase in complex with dasatinib

Abstract

ABL2/ARG (ABL-related gene) belongs to the ABL (Abelson tyrosine-protein kinase) family of tyrosine kinases. ARG plays important roles in cell morphogenesis, motility, growth and survival, and many of these biological roles overlap with the cellular functions of the ABL kinase. Chronic myeloid leukemia (CML) is associated with constitutive ABL kinase activation resulting from fusion between parts of the breakpoint cluster region (BCR) and ABL1 genes. Similarly, fusion of the ETV6 (Tel) and ARG genes drives some forms of T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). Dasatinib is a tyrosine kinase inhibitor used for the treatment of CML by inhibiting ABL, and while it also inhibits ARG, there is currently no structure of ARG in complex with dasatinib. Here, the co-crystal structure of the mouse ARG catalytic domain with dasatinib at 2.5 Å resolution is reported. Dasatinib-bound ARG is found in the DFG-in conformation although it is nonphosphorylated on the activation-loop tyrosine. In this structure the glycine-rich P-loop is found in a relatively open conformation compared with other known ABL family-inhibitor complex structures.

Molecular dynamics simulations of the conformational plasticity in the active pocket of salt-inducible kinase 2 (SIK2) multi-state binding with bosutinib

“…The piperazine of the dasatinib, which is similar to the 4-methylpiperazine group of bosutinib, also showed fluctuations. This piperazine region was a surface-exposed portion of the inhibitors [ [11] , [12] , [96] ]. However, the fragment in the solvent environment can be used to improve the bioavailability [ [97] , [98] ].…”

Dasatinib–SIK2 Binding Elucidated by Homology Modeling, Molecular Docking, and Dynamics Simulations

“…Earlier experimental studies corroborated this finding for ABL kinases. 34 , 84 − 86 Therefore, we did not run the simulation to evaluate the H2 molecule. G2, G3, and G4 were similar in terms of ligand binding.…”

Expression differences of miR-142-5p between treatment-naïve chronic myeloid leukemia patients responding and non-responding to imatinib therapy suggest a link to oncogenic ABL2, SRI, cKIT and MCL1 signaling pathways critical for development of therapy resistance

“…Subsequently, an extensive literature search was performed to evaluate the role of the suggested genes in context with CML. The following resulting five potential target genes with clear links to CML and CML-related pathways, cell survival and chemoresistance were selected for further interaction analysis via reporter gene assays: cKIT , a survival factor in CML cells, whose mutations contribute to poorer prognosis of CML patients, MCL1 , coding for an anti-apoptotic protein often overexpressed in CML, ABL2 , known to be upregulated in CML disease progression and potentially contributing to imatinib resistance, SHC4 , involved in activation of BCR-ABL1 and cKIT downstream pathways, and SRI associated with multidrug resistance in various tumour types (for further references, see Additional file 1 : Table S2) [ 21 , 31 , 40 , 49 , 57 ].…”

“…6 ). ABL2 , a member of the Abelson family of non-receptor tyrosine kinases, was identified as target of miR-142-5p in the present study and is known to be upregulated in CML disease progression [ 21 – 23 ]. By regulating cytoskeleton rearrangement, invasiveness of neoplastic cells and expression of matrix metalloproteinases (MMPs), it plays a substantial role in the BCR-ABL1 signaling network and is described to be involved in the acquisition of chemotherapy resistance in diverse solid tumors [ 23 , 24 ].…”

“…Target genes of interest were further evaluated by literature search focusing on their involvement in CML, leukemia, CML linked pathways and chemoresistance with a minimum of 10 publications each. These genes were transferred to further functional analysis, namely: ABL2 ( abelson murine leukemia viral oncogene homolog 2 [ 21 – 30 ]), cKIT ( KIT proto-oncogene receptor tyrosine kinase [ 4 , 31 – 39 ]), MCL1 ( myeloid cell leukemia 1 [ 7 , 40 – 48 ]), SHC4 ( src homology 2 domain containing family, member 4 [ 4 , 23 , 49 – 56 ]) and SRI ( sorcin [ 50 , 57 – 65 ]).…”