Fragment-sized and bidentate (immuno)proteasome inhibitors derived from cysteine and threonine targeting warheads
Povzetek
Constitutive- and immunoproteasomes are part of the ubiquitin–proteasome system (UPS), which is responsible for the protein homeostasis. Selective inhibition of the immunoproteasome offers opportunities for the treatment of numerous diseases, including inflammation, autoimmune diseases, and hematologic malignancies. Although several inhibitors have been reported, selective nonpeptidic inhibitors are sparse. Here, we describe two series of compounds that target both proteasomes. First, benzoxazole-2-carbonitriles as fragment-sized covalent immunoproteasome inhibitors are reported. Systematic substituent scans around the fragment core of benzoxazole-2-carbonitrile led to compounds with single digit micromolar inhibition of the β5i subunit. Experimental and computational reactivity studies revealed that the substituents do not affect the covalent reactivity of the carbonitrile warhead, but mainly influence the non-covalent recognition. Considering the small size of the inhibitors, this finding emphasizes the importance of the non-covalent recognition step in the covalent mechanism of action. As a follow-up series, bidentate inhibitors are disclosed, in which electrophilic heterocyclic fragments, i.e., 2-vinylthiazole, benzoxazole-2-carbonitrile, and benzimidazole-2-carbonitrile were linked to threonine-targeting (R)-boroleucine moieties. These compounds were designed to bind both the Thr1 and β5i-subunit-specific residue Cys48. However, inhibitory activities against (immuno)proteasome subunits showed that bidentate compounds inhibit the β5, β5i, β1, and β1i subunits with submicromolar to low-micromolar IC50 values. Inhibitory assays against unrelated enzymes showed that compounds from both series are selective for proteasomes. The presented nonpeptidic and covalent derivatives are suitable hit compounds for the development of either β5i-selective immunoproteasome inhibitors or compounds targeting multiple subunits of both proteasomes.
Ključne besede
immunoproteasome;benzoxazole-2-carbonitriles;bidentate covalent inhibitors;fragments;non-covalent recognition;
Podatki
| Jezik: | Angleški jezik |
|---|---|
| Leto izida: | 2021 |
| Tipologija: | 1.01 - Izvirni znanstveni članek |
| Organizacija: | UL FFA - Fakulteta za farmacijo |
| UDK: | 615.4:54 |
| COBISS: |
88025091
|
| ISSN: | 2073-4409 |
| Št. ogledov: | 91 |
| Št. prenosov: | 31 |
| Ocena: | 0 (0 glasov) |
| Metapodatki: |
|
Ostali podatki
| Sekundarni jezik: | Slovenski jezik |
|---|---|
| Sekundarne ključne besede: | Farmacevtska kemija; |
| Vrsta dela (COBISS): | Članek v reviji |
| Strani: | str. 1-20 |
| Letnik: | ǂVol. ǂ10 |
| Zvezek: | ǂiss. ǂ12 |
| Čas izdaje: | 2021 |
| DOI: | 10.3390/cells10123431 |
| ID: | 15327510 |
Priporočena dela:
Fragment-sized and bidentate (immuno)proteasome inhibitors derived from cysteine and threonine targeting warheads
2021,
ni podatka o podnaslovu
Bromo-cyclobutenaminones as new covalent UDP-N-acetylglucosamine enolpyruvyl transferase (murA) inhibitors
2020,
ni podatka o podnaslovu
Psoralen derivatives as inhibitors of mycobacterium tuberculosis proteasome
2020,
ni podatka o podnaslovu
Synthesis and biochemical evaluation of warhead-decorated psoralens as (immuno)proteasome inhibitors
2021,
ni podatka o podnaslovu
Molecular dynamics-derived pharmacophore model explaining the nonselective aspect of KV10.1 pore blockers
2021,
ni podatka o podnaslovu