Potent and Highly Selective Inhibitors of the Proteasome Trypsin-like Site by Incorporation of Basic Side Chain Containing Amino Acid Derived Sulfonyl Fluorides

Artschwager, Raik; Ward, David; Gannon, Susan; Brouwer, Arwin J.; Langemheen, Helmus van de; Kowalski, Hubert; Liskamp, Rob M. J.

doi:10.1021/acs.jmedchem.8b00685

Cited by 53 publications

(37 citation statements)

References 27 publications

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“…Despite covalent-reversible inhibitors of the proteasome representing the first class of proteasome inhibitors, e. g. peptidic boronic acids and aldehydes, the drug development of reversible binding warheads has remained underexplored over the last decade, focusing instead on irreversible acting warheads such as epoxyketones and sulfonyl fluorides. [37][38][39] Furthermore, explorations of structure-activity relationships of inhibitors targeting the primed site of β5 have been reported only occasionally. Our group previously reported the identification of ketoamide 7 that displays increased inhibitory activity compared to unsubstituted phenyl ketoamide 6 and allows for subsequent modification occupying the S1' pocket.…”

Section: Discussionmentioning

confidence: 99%

Cell‐Based Optimization of Covalent Reversible Ketoamide Inhibitors Bridging the Unprimed to the Primed Site of the Proteasome β5 Subunit

et al. 2019

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The ubiquitin‐proteasome system (UPS) is an established therapeutic target for approved drugs to treat selected hematologic malignancies. While drug discovery targeting the UPS focuses on irreversibly binding epoxyketones and slowly‐reversibly binding boronates, optimization of novel covalent‐reversibly binding warheads remains largely unattended. We previously reported α‐ketoamides to be a promising reversible lead motif, yet the cytotoxic activity required further optimization. This work focuses on the lead optimization of phenoxy‐substituted α‐ketoamides combining the structure‐activity relationships from the primed and the non‐primed site of the proteasome β5 subunit. Our optimization strategy is accompanied by molecular modeling, suggesting occupation of P1′ by a 3‐phenoxy group to increase β5 inhibition and cytotoxic activity in leukemia cell lines. Key compounds were further profiled for time‐dependent inhibition of cellular substrate conversion. Furthermore, the α‐ketoamide lead structure 27 does not affect escape response behavior in Danio rerio embryos, in contrast to bortezomib, which suggests increased target specificity.

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Section: Discussionmentioning

confidence: 99%

Cell‐Based Optimization of Covalent Reversible Ketoamide Inhibitors Bridging the Unprimed to the Primed Site of the Proteasome β5 Subunit

et al. 2019

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“…The unique properties observed with sulfonyl fluorides could be ascribed to (i) the right balance of inherent electrophilic reactivity of S VI –F and stability under physiological aqueous conditions, and (ii) the proton (H + )-mediated reactivity-switch-on mechanism that makes its reactivity sensitive to the microenvironment of the binding site, and thus allows a site-specific targeting under various chemical and biological contexts 2,12–14 . The successful identification of their highly selective inhibition activity has boosted a fast-growing research interest in recent years to develop enzyme inhibitors or chemical probes based on sulfonyl fluorides 12–26 . However, the development in this area is significantly hampered by the limited availability of sulfonyl fluorides 12–14 .…”

Section: Introductionmentioning

confidence: 99%

“…However, the development in this area is significantly hampered by the limited availability of sulfonyl fluorides 12–14 . The potential observed with aliphatic sulfonyl fluorides, in particular the peptide-type inhibitors 12,22–26 (Fig. 1a), has drawn our attention from a synthetic point of view.…”

Section: Introductionmentioning

confidence: 99%

A rapid access to aliphatic sulfonyl fluorides

Yang

et al. 2019

Nat Commun

105

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The past few years have witnessed a fast-growing research interest on the study of sulfonyl fluorides as reactive probes in chemical biology and molecular pharmacology, which raises an urgent need for the development of effective synthetic methods to expand the toolkit. Herein, we present the invention of a facile and general approach for the synthesis of aliphatic sulfonyl fluorides via visible-light-mediated decarboxylative fluorosulfonylethylation. The method is based on abundant carboxylic acid feed stock, applicable to various alkyl carboxylic acids including primary, secondary, and tertiary acids, and is also suitable for the modification of natural products like amino acids, peptides, as well as drugs, forging a rapid, metal-free approach to build sulfonyl fluoride compound libraries of considerable structural diversity. Further diversification of the SO 2 F-containing products is also demonstrated, which allows for access to a range of pharmaceutically important motifs such as sultam, sulfonate, and sulfonamide.

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“…However, these compounds, which are characterized by a sulfonyl fluoride as the C-terminal electrophile, a basic P1 residue, and a free N terminus, display limited preference for either β2c or β2i. 14 In addition, Kezar Life Sciences developed an epoxyketone inhibitor with moderate selectivity for human β2i. 11…”

Section: Introductionmentioning

confidence: 99%

Structure-Based Design of Inhibitors Selective for Human Proteasome β2c or β2i Subunits

Xin¹,

Huber

Bruin³

et al. 2019

J. Med. Chem.

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Subunit-selective proteasome inhibitors are valuable tools to assess the biological and medicinal relevance of individual proteasome active sites. Whereas the inhibitors for the β1c, β1i, β5c, and β5i subunits exploit the differences in the substrate-binding channels identified by X-ray crystallography, compounds selectively targeting β2c or β2i could not yet be rationally designed because of the high structural similarity of these two subunits. Here, we report the development, chemical synthesis, and biological screening of a compound library that led to the identification of the β2c- and β2i-selective compounds LU-002c (4; IC50 β2c: 8 nM, IC50 β2i/β2c: 40-fold) and LU-002i (5; IC50 β2i: 220 nM, IC50 β2c/β2i: 45-fold), respectively. Co-crystal structures with β2 humanized yeast proteasomes visualize protein–ligand interactions crucial for subunit specificity. Altogether, organic syntheses, activity-based protein profiling, yeast mutagenesis, and structural biology allowed us to decipher significant differences of β2 substrate-binding channels and to complete the set of subunit-selective proteasome inhibitors.

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Potent and Highly Selective Inhibitors of the Proteasome Trypsin-like Site by Incorporation of Basic Side Chain Containing Amino Acid Derived Sulfonyl Fluorides

Cited by 53 publications

References 27 publications

Cell‐Based Optimization of Covalent Reversible Ketoamide Inhibitors Bridging the Unprimed to the Primed Site of the Proteasome β5 Subunit

Cell‐Based Optimization of Covalent Reversible Ketoamide Inhibitors Bridging the Unprimed to the Primed Site of the Proteasome β5 Subunit

A rapid access to aliphatic sulfonyl fluorides

Structure-Based Design of Inhibitors Selective for Human Proteasome β2c or β2i Subunits

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