Structure-Based Development of Anticancer Drugs

Faig, M.; Bianchet, M.A.; Winski, Shannon L.; Hargreaves, Robert H J; Moody, Christopher J.; Hudnott, Anna R.; Ross, David; Amzel, L. Mario

doi:10.1016/s0969-2126(01)00636-0

Cited by 81 publications

(28 citation statements)

References 24 publications

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“…When comparing the quinone propionic acids (R 2 –R 4 = CH 3 ) with increasing size of the substituent at R 1 (H < CH 3 < CH 3 O), the K m increases, as expected for steric interactions between the quinone ring and the hNQO1 binding motif that result in an unfavorable alignment and position of the quinone ring in the active site. 35 Interestingly, V max decreases with increased size of R 1 substituent on the quinone propionic acid ring. This is quite evident when comparing the Q H -COOH, Q MeO -COOH, and Q Me -COOH species, as the V max of the hydrogen variant (83 µmol·min −1 ·mg −1 ) is roughly two times greater than that of the methyl-substituted quinone propionic acid (38 µmol·min −1 ·mg −1 ) and the methoxy derivative (42 µmol·min −1 ·mg −1 ).…”

Section: Resultsmentioning

confidence: 99%

“…Although there exists a good number of reports on structure-relationship activity 49–56 and docking studies of NQO1 inhibitors and substrates for anticancer therapy, 14, 35, 57–62 there is only one published report that provides Michaelis constant ( K m ) and maximum velocity ( V max ) values for the interaction of human NAD(P)H:quinone oxidoreductase-1 with a simple quinone. 44 In addition, the significant differences in reactivity of human NQO1 and rat NQO1 with specific quinone species 63–65 suggest limited applicability of structure-reactivity relationship predictions based on rat NQO1.…”

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confidence: 99%

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Human NAD(P)H:Quinone Oxidoreductase Type I (hNQO1) Activation of Quinone Propionic Acid Trigger Groups

et al. 2012

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NAD(P)H:quinone oxidoreductase type I (NQO1) is a target enzyme for triggered delivery of drugs at inflamed tissue and tumor sites, particularly those that challenge traditional therapies. Prodrugs, macromolecules, and molecular assemblies possessing trigger groups that can be cleaved by environmental stimuli are vehicles with the potential to yield active drug only at prescribed sites. Furthermore, quinone propionic acids (QPAs) covalently attached to prodrugs or liposome surfaces can be removed by application of a reductive trigger stimulus, such as that from NQO1; their rates of reductive activation should be tunable via QPA structure. We explored in detail the recombinant human NAD(P)H:quinone oxidoreductase type I (rhNQO1)-catalyzed NADH reduction of a family of substituted QPAs and obtained high precision kinetic parameters. It is found that small changes in QPA structure—in particular, single atom and function group substitutions on the quinone ring at R1—lead to significant impacts on the Michaelis constant (Km), maximum velocity (Vmax), catalytic constant (kcat), and catalytic efficiency (kcat/Km). Molecular docking simulations demonstrate that alterations in QPA structure result in large changes in QPA alignment and placement with respect to the flavin isoalloxazine ring in the active site of rhNQO1; a qualitative relationship exists between the kinetic parameters and the depth of QPA penetration into the rhNQO1 active site. From a quantitative perspective, a very good correlation is observed between log(kcat/Km) and the molecular-docking-derived distance between flavin hydride donor site and quinone hydride acceptor site in the QPAs, an observation that is in agreement with developing theories. The comprehensive kinetic and molecular modeling knowledge obtained for the interaction of recombinant human NQO1 with the quinone propionic acid analogues provides insight into the design and implementation of the QPA trigger groups for drug delivery applications.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Human NAD(P)H:Quinone Oxidoreductase Type I (hNQO1) Activation of Quinone Propionic Acid Trigger Groups

et al. 2012

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“…This implies that ligand dynamics is likely involved in the mechanism of partial NR agonism. In terms of non-NR proteins, differences in binding modes for similar compounds have been noted (Teague, 2003) in crystal structures of transthyretin (Faig et al, 2001) and NAD(P)H:Quinone Oxidoreductase 1 (Faig et al, 2001), where similar ligands also display flipped binding modes. Technologically related to our work, a ligand-detected NMR study revealed that a single ligand can have multiple binding modes when bound to riboflavin synthase, whereas another ligand that binds the same protein has only one binding mode (Scheuring et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Ligand and Receptor Dynamics Contribute to the Mechanism of Graded PPARγ Agonism

et al. 2012

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SUMMARY Ligand binding to proteins is not a static process, but rather involves a number of complex dynamic transitions. A flexible ligand can change conformation upon binding its target. The conformation and dynamics of a protein can change to facilitate ligand binding. The conformation of the ligand, however, is generally presumed to have one primary binding mode, shifting the protein conformational ensemble from one state to another. We report solution NMR studies that reveal peroxisome proliferator-activated receptor γ (PPARγ) modulators can sample multiple binding modes manifesting in multiple receptor conformations in slow conformational exchange. Our NMR, hydrogen/deuterium exchange and docking studies reveal that ligand-induced receptor stabilization and binding mode occupancy correlate with the graded agonist response of the ligand. Our results suggest that ligand and receptor dynamics affect the graded transcriptional output of PPARγ modulators.

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“…For docking purposes, the crystallographic coordinates of the human NQO1 complex with 3-(hydroxymethyl)-5-(2-methylaziridin-1-yl)-1-methyl-2-phenylindole-4,7-dione ( 25 ) were obtained from the Brookhaven Database (PDB code 1H69 33 and resolution 1.86Ǻ) and was edited accordingly to provide a monomer of the protein. The protein complex was then minimized within Sybyl 7.3 (Tripos Ltd., St Louis) while holding all heavy atoms stationary.…”

Section: Methodsmentioning

confidence: 99%

Synthesis of New Quinolinequinone Derivatives and Preliminary Exploration of their Cytotoxic Properties

et al. 2013

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A series of 7-amino- and 7-acetamidoquinoline-5,8-diones with aryl substituents at the 2-position were synthesized, characterized and evaluated as potential NAD(P)H:quinone oxidoreductase (NQO1)-directed antitumor agents. The synthesis of lavendamycin analogs is illustrated. Metabolism studies demonstrated that 7-amino-analogues were generally better substrates for NQO1 than 7-amido-analogues as were compounds with smaller heteroaromatic substituents at the C-2 position. Surprisingly, only two compounds, 7-acetamido-2-(8’-quinolinyl)quinoline-5,8-dione (11) and 7-amino-2-(2-pyridinyl)quinoline-5,8-dione (23) showed selective cytotoxicity toward the NQO1-expressing MDA468-NQ16 breast cancer cells versus the NQO1-null MDA468-WT cells. For all other compounds, NQO1 protected against quinoline-5,8-dione cytotoxicity. Compound 22 showed a potent activity against human breast cancer cells expressing or not expressing NQO1 with IC50 values of respectively 190 nM and 140 nM and a low NQO1 mediated reduction rate, which suggests that the mode of action of 22 differs from lavendamycin and involves an unidentified target(s).

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Structure-Based Development of Anticancer Drugs

Cited by 81 publications

References 24 publications

Human NAD(P)H:Quinone Oxidoreductase Type I (hNQO1) Activation of Quinone Propionic Acid Trigger Groups

Human NAD(P)H:Quinone Oxidoreductase Type I (hNQO1) Activation of Quinone Propionic Acid Trigger Groups

Ligand and Receptor Dynamics Contribute to the Mechanism of Graded PPARγ Agonism

Synthesis of New Quinolinequinone Derivatives and Preliminary Exploration of their Cytotoxic Properties

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