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A new solvate of afatinib, a specific inhibitor of the ErbB family of tyrosine kinases.

ABSTRACT: Afatinib (systematic name: N-{4-(3-chloro-4-fluoro-anilino)-7-[(tetra-hydro-furan-3-yl)-oxy]quinazolin-6-yl}-4-(di-methyl-amino)-but-2-enamide), is a specific in-hibitor of the ErbB family of tyrosine kinases. The free base form crystallizes from aceto-nitrile as a mixed water-aceto-nitrile solvent, C₂₄H₂₅ClFN₅O₃·0.25C₂H₃N·2H₂O. It crystallizes with two independent mol-ecules (A and B) in the asymmetric unit of the chiral space group P42₁2, but exhibits close to perfect pseudo-inversion symmetry, emulating P4/ncc that relates the two mol-ecules to each other. Exact inversion symmetry is however broken by swapping of oxygen and CH₂ moieties of the outer tetra-hydro-furanyl substituents of the two independent mol-ecules. This can, in turn, be traced back to C-H?N and C-H?O inter-actions of the aceto-nitrile solvent mol-ecules with the tetra-hydro-furan oxygen and CH₂ units. In the crystal, neighboring mol-ecules are connected via N-H?O hydrogen bonds between the secondary amine and the amide keto O atom. Additional hydrogen bonds are formed through the water solvent mol-ecules, which are engaged in O-H?O and O-H?N hydrogen bonds connecting to the di-methyl-amino N atom, the amide keto O atom, and one of the quinazoline N atoms of a neighboring mol-ecule, leading to an intricate three-dimensional hydrogen-bonded superstructure. There are two types of channels stretching along the direction of the c axis; one along the fourfold rotational axis, occupied by aceto-nitrile solvent mol-ecules situated on that axis, and parallel channels which are not occupied by any solvent.

SUBMITTER: Zeller M

PROVIDER: S-EPMC5347068 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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A new solvate of afatinib, a specific inhibitor of the ErbB family of tyrosine kinases.

Zeller Matthias M de Araujo Gabriel Lima Barros GL Parker Trev T Singh Rai Amrinder A Byrn Stephen R SR

Acta crystallographica. Section E, Crystallographic communications 20170221 Pt 3

Afatinib (systematic name: N-{4-(3-chloro-4-fluoro-anilino)-7-[(tetra-hydro-furan-3-yl)-oxy]quinazolin-6-yl}-4-(di-methyl-amino)-but-2-enamide), is a specific in-hibitor of the ErbB family of tyrosine kinases. The free base form crystallizes from aceto-nitrile as a mixed water-aceto-nitrile solvent, C24H25ClFN5O3·0.25C2H3N·2H2O. It crystallizes with two independent mol-ecules (A and B) in the asymme ...[more]

PMID: 28316823

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Project description:BACKGROUND: The epidermal growth factor receptor kinases, or ErbB kinases, belong to a large sub-group of receptor tyrosine kinases (RTKs), which share a conserved catalytic core. The catalytic core of ErbB kinases have functionally diverged from other RTKs in that they are activated by a unique allosteric mechanism that involves specific interactions between the kinase core and the flanking Juxtamembrane (JM) and COOH-terminal tail (C-terminal tail). Although extensive studies on ErbB and related tyrosine kinases have provided important insights into the structural basis for ErbB kinase functional divergence, the sequence features that contribute to the unique regulation of ErbB kinases have not been systematically explored. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we use a Bayesian approach to identify the selective sequence constraints that most distinguish ErbB kinases from other receptor tyrosine kinases. We find that strong ErbB kinase-specific constraints are imposed on residues that tether the JM and C-terminal tail to key functional regions of the kinase core. A conserved RIxKExE motif in the JM-kinase linker region and a glutamine in the inter-lobe linker are identified as two of the most distinguishing features of the ErbB family. While the RIxKExE motif tethers the C-terminal tail to the N-lobe of the kinase domain, the glutamine tethers the C-terminal tail to hinge regions critical for inter-lobe movement. Comparison of the active and inactive crystal structures of ErbB kinases indicates that the identified residues are conformationally malleable and can potentially contribute to the cis regulation of the kinase core by the JM and C-terminal tail. ErbB3, and EGFR orthologs in sponges and parasitic worms, diverge from some of the canonical ErbB features, providing insights into sub-family and lineage-specific functional specialization. CONCLUSION/SIGNIFICANCE: Our analysis pinpoints key residues for mutational analysis, and provides new clues to cancer mutations that alter the canonical modes of ErbB kinase regulation.

Project description:Protein kinases are enzymes that catalyze the covalent transfer of the γ-phosphate of an adenosine triphosphate (ATP) molecule onto a tyrosine, serine, threonine, or histidine residue in the substrate and thus send a chemical signal to networks of downstream proteins. They are important cellular signaling enzymes that regulate cell growth, proliferation, metabolism, differentiation, and migration. Unregulated protein kinase activity is often associated with a wide range of diseases, therefore making protein kinases major therapeutic targets. A prototypical system of central interest to understand the regulation of kinase activity is provided by tyrosine kinase c-Src, which belongs to the family of Src-related non-receptor tyrosine kinases (SFKs). Although the broad picture of autoinhibition via the regulatory domains and via the phosphorylation of the C-terminal tail is well characterized from a structural point of view, a detailed mechanistic understanding at the atomic-level is lacking. Advanced computational methods based on all-atom molecular dynamics (MD) simulations are employed to advance our understanding of tyrosine kinase activation. The computational studies suggest that the isolated kinase domain (KD) is energetically most favorable in the inactive conformation when the activation loop (A-loop) of the KD is not phosphorylated. The KD makes transient visits to a catalytically competent active-like conformation. The process of bimolecular trans-autophosphorylation of the A-loop eventually locks the KD in the active state. Activating point mutations may act by slightly increasing the population of the active-like conformation, enhancing the availability of the A-loop to be phosphorylated. The Src-homology 2 (SH2) and Src-homology 3 (SH3) regulatory domains, depending upon their configuration, either promote the inactive or the active state of the kinase domain. In addition to the roles played by the SH3, SH2, and KD, the Src-homology 4-Unique domain (SH4-U) region also serves as a key moderator of substrate specificity and kinase function. Thus, a fundamental understanding of the conformational propensity of the SH4-U region and how this affects the association to the membrane surface are likely to lead to the discovery of new intermediate states and alternate strategies for inhibition of kinase activity for drug discovery. The existence of a multitude of KD conformations poses a great challenge aimed at the design of specific inhibitors. One promising computational strategy to explore the conformational flexibility of the KD is to construct Markov state models from aggregated MD data.

Dataset Information

A new solvate of afatinib, a specific inhibitor of the ErbB family of tyrosine kinases.

Publications

A new solvate of afatinib, a specific inhibitor of the ErbB family of tyrosine kinases.

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