Structures of the Cancer-Related Aurora-A, FAK, and EphA2 Protein Kinases from Nanovolume Crystallography

Nowakowski, Jacek; Cronin, Ciarán N.; McRee, Duncan E.; Knuth, Mark W.; Nelson, Christine; Pavletich, Nikola P.; Rogers, Joseph M.; Sang, Bi‐Ching; Scheibe, Daniel; Swanson, Ronald V.; Thompson, Devon A.

doi:10.1016/s0969-2126(02)00907-3

Cited by 192 publications

(166 citation statements)

References 49 publications

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“…The kinase domain of human Plk1 was therefore modelled using the SWISS-MODEL server (Guex and Peitsch, 1997) based on the crystal structures of Aurora-A (Bayliss et al, 2003) (PDB codes 1Ol5 and 1Ol7), (Nowakowski et al, 2002) (PDB code 1MQ4), Aurora-B (Cheetham et al, 2002) (PDB code 1MUO), and Akt/ PKB (Yang et al, 2002) (PDB code 1O6K) ( Figure 5a, b). This Plk1 model was subsequently used as a template to model the Plk2, Plk3, and Plk4 kinase domains (Figure 5c-e).…”

Section: Model Of the Plk Kinase Domainmentioning

confidence: 99%

“…(a) A ribbon figure of a model of the Plk1 kinase domain (residues 48-309) is shown in two orthogonal views and with the N-and Cterminal lobes colored green and blue, respectively. The model of the core kinase domain is based primarily on the structures of Aurora-A and -B (Bayliss et al, 2003;Cheetham et al, 2002;Nowakowski et al, 2002). The activation loop was modelled in an active conformation using the structure of the Akt/PKB : AMP-PNP : GSK3-peptide ternary complex (Yang et al, 2002).…”

Section: Model Of the Plk Kinase Domainmentioning

confidence: 99%

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Structure and function of Polo-like kinases

2005

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Polo-like kinases play critical roles during multiple stages of cell cycle progression. All Polo-like kinases contain an N-terminal Ser/Thr kinase catalytic domain and a Cterminal region that contains one or two Polo-boxes. For Polo-like kinase 1, 2, and 3, and their homologs, the entire C-terminal region, including both Polo-boxes, functions as a single modular phosphoserine/threonine-binding domain known as the Polo-box domain (PBD). In the absence of a bound substrate, the PBD inhibits the basal activity of the kinase domain. Phosphorylation-dependent binding of the PBD to its ligands releases the kinase domain, while simultaneously localizing Polo-like kinases to specific subcellular structures. These observations suggest two different models for how the PBD integrates signals arising from other mitotic kinases to target the activated kinase towards distinct substrates. The recent X-ray crystal structures of the PBD provide insights into the structural basis for PBD function and kinase regulation. Molecular modelling of the structure of the isolated kinase domain reveals a potential basis for motif-dependent substrate specificity.

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Section: Model Of the Plk Kinase Domainmentioning

confidence: 99%

Section: Model Of the Plk Kinase Domainmentioning

confidence: 99%

Structure and function of Polo-like kinases

2005

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“…A number of crystal structures of Aurora A in different conformations with ATP analogues have been published [45][46][47][48] . A crystal structure of Aurora A complexed with a small molecule inhibitor from the pyrimidinoquinazoline series adopts an inactive conformation with the displacement of the DFG motif (DFG-out) [45] .…”

Section: Discussionmentioning

confidence: 99%

Structural studies of B-type Aurora kinase inhibitors using computational methods

et al. 2010

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“…At this time, the 2.0 Å resolution cocrystal structure of Itk in complex with compound 3e, one of our initial thiazolopyridine hits, was obtained (Figure 3a). 24 Compound 3e binds in the ATP-binding domain of Itk; the aminothiazolopyridine core makes two H-bonding interactions with the backbone carbonyl and NH of Met438 in the hinge region and is flanked by the side chains of Ala389 and Leu489. Compound 3e appears to adopt a conformation stabilized by a water-bridged hydrogenbonding network between the methoxy, pyridinyl, and cyclohexanol hydroxyl groups.…”

mentioning

confidence: 99%

“…(a) Cocrystal structure of compound 3e bound to Itk kinase domain. 24 Omit map electron density (at 3σ) is shown. (b) Connolly surfaces of compound 3e (green) and neighboring residue (Val419) of cocrystal structure overlaid with the equivalent AurA residue (Leu194, colored purple) defined from selected AurA crystal structures.…”

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confidence: 99%

Identification of a Novel and Selective Series of Itk Inhibitors via a Template-Hopping Strategy

Alder

Ambler

Campbell

et al. 2013

ACS Med. Chem. Lett.

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Inhibition of Itk potentially constitutes a novel, nonsteroidal treatment for asthma and other T-cell mediated diseases. In-house kinase cross-screening resulted in the identification of an aminopyrazole-based series of Itk inhibitors. Initial work on this series highlighted selectivity issues with several other kinases, particularly AurA and AurB. A template-hopping strategy was used to identify a series of aminobenzothiazole Itk inhibitors, which utilized an inherently more selective hinge binding motif. Crystallography and modeling were used to rationalize the observed selectivity. Initial exploration of the SAR around this series identified potent Itk inhibitors in both enzyme and cellular assays. KEYWORDS: Interleukin-2 inducible tyrosine kinase, Itk, kinase inhibitors, aminobenzothiazole, template hopping, kinase selectivity I nterleukin-2 inducible tyrosine kinase (Itk) is a nonreceptor protein tyrosine kinase that is expressed in T cells, mast cells, and NK cells. Itk plays an important role in signaling, downstream of the T cell receptor in response to antigen presentation by MHC proteins, and its inhibition leads to reduced levels of key inflammatory cytokines. 1 In vivo experiments with Itk knockout mice suggest a role for Itk inhibitors in the treatment of asthma. 2 A number of Itk inhibitor series have been disclosed in the literature with a focus on achieving broad kinase selectivity as well as good levels of cellular activity; both of which have been relatively challenging for this tyrosine kinase. 3−6 Despite these publications, there have been no reports of an Itk inhibitor entering clinical trials and hypotheses regarding its clinical potential remain untested. 7 In-house cross screening resulted in the identification of a series of aminopyrazoles as inhibitors of Itk. This series was of particular interest to us as, in contrast to previous series investigated, compounds in this series displayed a promising level of ligand efficiency (LE = 0.36, compound 1). 8 An initial X-ray crystal structure of compound 1 (Figure 1) in Itk confirmed the aminopyrazole group was binding to the hinge region of Itk and utilizing a three-point hinge binding motif. Initial optimization work focused on the pyrimidine 2-position and the pendant group of the pyrazole. However, these modifications did not produce compounds with the desired 100-fold selectivity margin over key kinases, namely, LCK, AurA, and AurB. Compound 2 (Figure 1) represents the best combination of potency and selectivity achieved with this series. Substantial SAR knowledge had been built up around the other parts of the template at this stage, and it was hypothesized that replacing the aminopyrazole motif with an inherently more selective hinge-binder could be an efficient method of accessing novel and selective Itk inhibitors.A robust Itk crystallography system was not available at this time, and therefore a fragment based approach 9−11 using crystallography to identify new hinge-binding groups was not

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Structures of the Cancer-Related Aurora-A, FAK, and EphA2 Protein Kinases from Nanovolume Crystallography

Cited by 192 publications

References 49 publications

Structure and function of Polo-like kinases

Structure and function of Polo-like kinases

Structural studies of B-type Aurora kinase inhibitors using computational methods

Identification of a Novel and Selective Series of Itk Inhibitors via a Template-Hopping Strategy

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