Synthesis and SAR of Pyrrolotriazine‐4‐one‐Based Eg5 Inhibitors.

Kim, Kyoung Soon; al., et

doi:10.1002/chin.200645167

Cited by 9 publications

(21 citation statements)

References 1 publication

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“…Alignment of PDB ID No. 2gm1 (34) and 1ii6 (15), rendered using PyMol Software (Schrodinger, LLC, New York, NY). ADP is shown in CPK format with ribose oxygens labeled, the a3 helix and Switch I elements are blue, and L5 is red except for the seven residues that were deleted in the DL5 constructs, which are shown in green.…”

Section: Sample Preparationmentioning

confidence: 99%

“…The Eg5 neck linker conformation has been shown to be tightly coupled to the nucleotide state when the motor is bound to MTs, transitioning between a conformation that is believed to be roughly perpendicular to the MT axis (15) and a conformation that is fully docked (14,34). We sought to detect these changes by EPR spectroscopy using L360C-MSL-and V365C-MSL-labeled Eg5.…”

Section: Msl Bound To the Neck Linker Of Eg5 On Mts Is Immobilized Inmentioning

confidence: 99%

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The Conserved L5 Loop Establishes the Pre-Powerstroke Conformation of the Kinesin-5 Motor, Eg5

Larson

Naber

Cooke

et al. 2010

Biophysical Journal

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Kinesin superfamily motor proteins contain a structurally conserved loop near the ATP binding site, termed L5. The function of L5 is unknown, although several drug inhibitors of the mitotic kinesin Eg5 bind to L5. We used electron paramagnetic resonance spectroscopy (EPR) to investigate the function of L5 in Eg5. We site-specifically attached EPR probes to ADP, L5, and the neck linker element that docks along the enzymatic head to drive forward motility on microtubules (MTs). Nucleotide-dependent spectral mobility shifts occurred in all of these structural elements, suggesting that they undergo coupled conformational changes. These spectral shifts were altered by deletion of L5 or addition of S-trityl-l-cysteine (STLC), an allosteric inhibitor that binds to L5. In particular, EPR probes attached to the neck linker of MT-bound Eg5 shifted to a more immobilized component in the nucleotide-free state relative to the ADP-bound state, consistent with the neck linker docking upon ADP release. In contrast, after L5 deletion or STLC addition, EPR spectra were highly immobilized in all nucleotide states. We conclude that L5 undergoes a conformational change that enables Eg5 to bind to MTs in a pre-powerstroke state. Deletion or inhibition of L5 with the small-molecule inhibitor STLC blocks this pre-powerstroke state, forcing the Eg5 neck linker to dock regardless of the nucleotide state.

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Section: Sample Preparationmentioning

confidence: 99%

Section: Msl Bound To the Neck Linker Of Eg5 On Mts Is Immobilized Inmentioning

confidence: 99%

The Conserved L5 Loop Establishes the Pre-Powerstroke Conformation of the Kinesin-5 Motor, Eg5

Larson

Naber

Cooke

et al. 2010

Biophysical Journal

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“…27 Recently, a different ligand-protein conformation has been reported (2GM1), which has a larger hydrophobic pocket formed by the rotation of the side chains of Arg101 and Leu196 and which has also a ligand that possesses a (CH 2 ) 3 NH 2 side chain. 28 The ligands of the three complexes are depicted in Figure 1.…”

Section: S-trityl-l-cysteine Analogues As Inhibitorsmentioning

confidence: 99%

Structure–Activity Relationship of S-Trityl-l-Cysteine Analogues as Inhibitors of the Human Mitotic Kinesin Eg5

et al. 2008

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The human kinesin Eg5 is a potential drug target for cancer chemotherapy. Eg5 specific inhibitors cause cells to block in mitosis with a characteristic monoastral spindle phenotype. Prolonged metaphase block eventually leads to apoptotic cell death. S-trityl-L-cysteine (STLC) is a tight-binding inhibitor of Eg5 that prevents mitotic progression. It has proven antitumor activity as shown in the NCI 60 tumor cell line screen. It is of considerable interest to define the minimum chemical structure that is essential for Eg5 inhibition and to develop more potent STLC analogues. An initial structure-activity relationship study on a series of STLC analogues reveals the minimal skeleton necessary for Eg5 inhibition as well as indications of how to obtain more potent analogues. The most effective compounds investigated with substitutions at the para-position of one phenyl ring have an estimated K i (app) of 100 nM in vitro and induce mitotic arrest with an EC 50 of 200 nM.

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“…In recent years, several classes of KSP inhibitors have been reported [5–21] . The pharmacophore identification and binding mode analysis based on the reported KSP inhibitors have been presented in our previous studies [22,23] …”

Section: Introductionmentioning

confidence: 99%

CPUYJ039, a newly synthesized benzimidazole-based compound, is proved to be a novel inducer of apoptosis in HCT116 cells with potent KSP inhibitory activity

Jiang

Yang

Wu-tong

et al. 2011

Journal of Pharmacy and Pharmacology

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Synthesis and SAR of Pyrrolotriazine‐4‐one‐Based Eg5 Inhibitors.

Cited by 9 publications

References 1 publication

The Conserved L5 Loop Establishes the Pre-Powerstroke Conformation of the Kinesin-5 Motor, Eg5

The Conserved L5 Loop Establishes the Pre-Powerstroke Conformation of the Kinesin-5 Motor, Eg5

Structure–Activity Relationship of S-Trityl-l-Cysteine Analogues as Inhibitors of the Human Mitotic Kinesin Eg5

CPUYJ039, a newly synthesized benzimidazole-based compound, is proved to be a novel inducer of apoptosis in HCT116 cells with potent KSP inhibitory activity

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