Emerging trends in metalloprotein inhibition

Rouffet, Matthieu; Cohen, Seth M.

doi:10.1039/c0dt01743d

Cited by 66 publications

(50 citation statements)

References 66 publications

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“…Thioesters are inherently unstable in the reducing environment of the cell, suggesting that the active moiety is 8TQ . This extraordinary confluence of results underscores the uniqueness of the 8TQ moiety for potent and specific inhibition of JAMM enzymes, and highlights the remarkable power of our approach to identify a metalloenzyme inhibitor by screening a focused library of MBPs 15,16 .…”

Section: Resultsmentioning

confidence: 78%

Capzimin is a potent and specific inhibitor of proteasome isopeptidase Rpn11

et al. 2017

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The proteasome is a vital cellular machine that maintains protein homeostasis, which is of particular importance in multiple myeloma and possibly other cancers. Targeting proteasome 20S peptidase activity with bortezomib and carfilzomib has been widely used to treat myeloma. However, not all patients respond, and those that do eventually suffer relapse. Therefore, there is an urgent and unmet need to develop novel drugs that target proteostasis through different mechanisms. We identified quinoline-8-thiol (8TQ) as a first-in-class inhibitor of the proteasome 19S subunit Rpn11. A derivative of 8TQ, capzimin, shows >5-fold selectivity for Rpn11 over the related JAMM proteases and >2 logs less activity towards metalloenzymes. Capzimin stabilized proteasome substrates, induced an unfolded protein response, and blocked proliferation of cancer cells, including those resistant to bortezomib. Proteomic analysis revealed that capzimin stabilized a subset of polyubiquitinated substrates. Identification of capzimin offers an alternative path to develop proteasome inhibitors for cancer therapy.

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Section: Resultsmentioning

confidence: 78%

Capzimin is a potent and specific inhibitor of proteasome isopeptidase Rpn11

et al. 2017

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“…Metalloenzymes comprise a significant portion of known enzymes [1] and are promising as therapeutic targets [2] due to their roles in a variety of diseases and infections, including glaucoma [3], cancer [4], and HIV [5]. Metalloenzymes can be inhibited by small molecules possessing metal-binding pharmacophores (MBPs) that coordinate to the active site metal ion, resulting in a bioinorganic complex [6].…”

Section: Introductionmentioning

confidence: 99%

“…Metalloenzymes can be inhibited by small molecules possessing metal-binding pharmacophores (MBPs) that coordinate to the active site metal ion, resulting in a bioinorganic complex [6]. Historically, MBPs such as carboxylic acids, phosphates, thiols, and hydroxamic acids have been utilized, but in recent years a broader repertoire of pharmacophores has been investigated [2, 7–10]. However, a detailed understanding of how the coordination chemistry of these MBPs is influenced and altered by the metalloenzyme active site is still lacking.…”

Section: Introductionmentioning

confidence: 99%

Effect of donor atom identity on metal-binding pharmacophore coordination

et al. 2017

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The inhibition and binding of three metal-binding pharmacophores (MBPs), 2-hydroxycyclohepta-2,4,6-trien-1-one (tropolone), 2-mercaptopyridine-N-oxide (1,2-HOPTO), and 2-hydroxycyclohepta-2,4,6-triene-1-thione (thiotropolone) to human carbonic anhydrase II (hCAII) and a mutant protein hCAII L198G were investigated. These MBPs displayed bidentate coordination to the active site Zn(II) metal ion, but the MBPs respond to the mutation of L198G differently, as characterized by inhibition activity assays and X-ray crystallography. The L198G mutation increases the active site volume thereby decreasing the steric pressure exerted on MBPs upon binding, allowing changes in MBP coordination to be observed. When comparing the binding mode of tropolone to thiotropolone or 1,2-HOPTO (O,O versus O,S donor sets), structural modifications of the hCAII active site were shown to have a stronger effect on MBPs with an O,O versus O,S donor set. These findings were corroborated with density functional theory (DFT) calculations of model coordination complexes. These results suggest that the MBP binding geometry is a malleable interaction, particularly for certain ligands, and that the identity of the donor atoms still play a significant role in ligand coordination. Understanding underlying interactions between a MBP and a metalloenzyme active site may aid in the design and development of potent metalloenzyme inhibitors.

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“…Similarly, metalloproteins are essential to numerous biological processes and represent a broad class of validated clinical targets (10, 11). Metalloprotein inhibitors (MPi) are generally comprised of a metal-binding pharmacophore (MBP) and ‘backbone’ substituents (12). MPi are used to treat a variety of illnesses including hypertension, cancer, and infectious diseases, thereby have a significant impact on improving human health (12, 13).…”

Section: Introductionmentioning

confidence: 99%

“…Metalloprotein inhibitors (MPi) are generally comprised of a metal-binding pharmacophore (MBP) and ‘backbone’ substituents (12). MPi are used to treat a variety of illnesses including hypertension, cancer, and infectious diseases, thereby have a significant impact on improving human health (12, 13). However, despite their importance, MPi are underdeveloped compared to conventional small molecule therapeutics.…”

Section: Introductionmentioning

confidence: 99%

The effect of metalloprotein inhibitors on cellular metal ion content and distribution

et al. 2017

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With metalloproteins garnering increased interest as therapeutic targets, designing target-specific metalloprotein inhibitors (MPi) is of substantial importance. However, in many respects, the development and evaluation of MPi lags behind that of conventional small molecule therapeutics. Core concerns around MPi, such as target selectivity and potential disruption of metal ion homeostasis linger. Herein, we used a suite of analytical methods, including energy-dispersive X-ray spectroscopy (EDX), inductively coupled plasma atomic emission spectroscopy (ICP-OES), and synchrotron X-ray fluorescence microscopy (SXRF) to investigate the effect of several MPi on cellular metal ion distribution and homeostasis. The results reveal that at therapeutically relevant concentrations, the tested MPi have no significant effects on cellular metal ion content or distribution. In addition, the affinity of the metal-binding pharmacophore (MBP) utilized by the MPi does not have a substantial influence on the effect of the MPi on cellular metal distribution. These studies provide an important, original data set indicating that metal ion homeostasis is not notably perturbed by MPi, which should encourage the development of and aid in designing new MPi, guide MBP selection, and clarify the effect of MPi on the ‘metallome’.

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Emerging trends in metalloprotein inhibition

Cited by 66 publications

References 66 publications

Capzimin is a potent and specific inhibitor of proteasome isopeptidase Rpn11

Capzimin is a potent and specific inhibitor of proteasome isopeptidase Rpn11

Effect of donor atom identity on metal-binding pharmacophore coordination

The effect of metalloprotein inhibitors on cellular metal ion content and distribution

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