Indolo‐Phakellins as β5‐Specific Noncovalent Proteasome Inhibitors

Abstract

The proteasome represents an invaluable target for the treatment of cancer and autoimmune disorders. The application of proteasome inhibitors, however, remains limited to blood cancers because their reactive headgroups and peptidic scaffolds convey unfavorable pharmacodynamic properties. Thus, the discovery of more drug-like lead structures is indispensable. In this study, we present the first structure of the proteasome in complex with an indolo-phakellin that exhibits a unique noncovalent binding mode unparalleled by all hitherto reported inhibitors. The natural product inspired pentacyclic alkaloid binds solely and specificially into the spacious S3 subpocket of the proteasomal β5 substrate binding channel, gaining major stabilization through halogen bonding with the protein backbone. The presented compound provides an ideal scaffold for the structure-based design of subunit-specific nonpeptidic proteasome-blockers.

Substituted quinolines as noncovalent proteasome inhibitors

“…Examples of nonpeptidic noncovalent proteasome modulators include the phakellins, 25 oxadiazoles, 26 hydroxyureas, 24 imidazolines 27,28 sulfone or piperazine agents, 29 and tamoxifen derivatives. 30 …”

Structure-based design of human immuno- and constitutive proteasomes inhibitors

“…3-4) [18][19][20][21][22][23][24], and pseudopeptides [25][26][27] (Figure 2). Nonpeptidic noncovalent inhibitors have also been described (e. g. sulfonamides [28][29][30][31], hydroxyurea [32], 1,2,4-oxadiazoles [33], pyrazoles [34], phakellins [35], quinolines [36], psoralene [37]). The three approved covalent drugs inhibit mainly the β5 activity of the M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 4 catalytic core of the constitutive proteasome (cCP) but also that of the inducible immunoproteasome (iCP).…”

Identification of a β1/β2‐Specific Sulfonamide Proteasome Ligand by Crystallographic Screening

“…[9][10][11] Recently,t he discovery of N-hydroxyureas and alkaloids as proteasome inhibitors broadened the range of potential scaffolds. [12,13] In addition to the scientific literature,s ome innovative scaffolds have been revealed in patents, [14][15][16][17][18] but apart from these advances,the general structure of validated CP inhibitors has historically been limited to peptidic pharmacophores. [19,20] Concurrently,t he development of new proteasome blockers continues to be hampered by al ack of structural knowledge from ligands that target novel binding sites since common fluorescence-based screening methods suffer from two major limitations.F irst, the assays are susceptible to fluorescence quenching artifacts,thus resulting in ah igh number of false-positive or false-negative results.…”