Bafetinib (INNO-406) Mechanism
ABL-1 comprises of N-terminal and C-terminal parts. Specifically, the N-terminal half of the protein contains an N-terminal ‘cap’ for autoinhibition, an SH3 domain, an SH2 domain, and a tyrosine kinase domain. While the C-terminal half contains binding elements for SH3 domains, nuclear localization and export signals, a DNA binding functionality, and an actin binding domain. The inactive form of ABL-1 is stabilized by an association between the SH3 domain and the SH2-TK linker region, interactions of the N-terminal cap, as well as contributions from an N-terminal myristoyl group and phospholipids. The kinase domain is composed of N-lobe and C-lobe linked by a cleft. The ATP binding site and the activation loop are located in the pocket between the N- and C-lobe. [1]
Bafetinib is a 3-substituted benzamide derivative. The crystal structure indicates that Bafetinib binds in the active site of ABL-1 kinase domain. Specifically, the terminal pyrimidine ring of Bafetinib forms a hydrogen bond to the backbone of Met318 in the hinge region, and the central tolyl moiety occupies a region defined by a series of conserved residues, which makes a large contribution to the inhibitory activity. Besides, Bafetinib also makes interactions with the amino acids of ABL-1 by forming hydrogen bonds with Glu286, Thr315, Ile360, His361, and Asp381. In addition, the 3-substituted CF3 group occupies well the hydrophobic pocket formed by the hydrophobic amino acids Ile293, Leu298, Leu354, and Val379, and the resulting hydrophobic interactions also contribute to enhancing the inhibitory activity against ABL-1. [2]
References
[1] Nagar B, et al. Cell. 2003, 112(6), 859-871.
[2] Horio T, et al. Bioorg Med Chem Lett. 2007, 17(10), 2712-2717.
