Degrasyn Activates Proteasomal-Dependent Degradation of c-Myc

Abstract

c-Myc is a highly unstable transcription factor whose deregulation and increased expression are associated with cancer. Degrasyn, a small synthetic molecule, induces rapid degradation of c-Myc protein in MM-1 multiple myeloma and other tumor cell lines. Destruction of c-Myc by degrasyn requires the presence of a region of c-Myc between amino acid residues 316 and 378 that has not previously been associated with c-Myc stability. Degrasyn-induced degradation of c-Myc depends on proteasomes but is independent of the degron regions previously shown to be important for ubiquitinmediated targeting and proteasomal destruction of the protein. Degrasyn-dependent c-Myc proteolysis is not mediated by any previously identified c-Myc regulatory mechanism, does not require new protein synthesis, and does not depend on the nuclear localization of c-Myc. Degrasyn reduced c-Myc levels in A375 melanoma cells and in A375 tumors in nude mice, and this activity correlated with tumor growth inhibition. Together, these results suggest that degrasyn reduces the stability of c-Myc in vitro and in vivo through a unique signaling process that uses c-Myc domains not previously associated with c-Myc regulation. [Cancer Res 2007;67(8):3912-8]

c-Myc protein is degraded in response to UV irradiation

“…Recently, a new degradation route of c-MYC has been described that is induced by the synthetic molecule degrasyn, depends on the proteasome and requires a region of c-MYC between aa 316 and 378. 57 Since this region corresponds to the segment deleted in our ΔF construct which is still degraded after UV, we conclude that different domains are required for degrasyn and UV-light to channel c-MYC into the proteasome.…”

“…The wild-type, ΔMBI (aa [45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63] and ΔMBII (aa 129-143) N-terminally FLAG tagged c-MYC2 coding pcDNA3 plasmids were kindly provided by Dr B. Lüscher (Institut für Biochemie, Aachen, Germany). ΔMBIII (aa 129-143), ΔA (aa 1-63), ΔB (aa 64-126), ΔC (aa 127-189), ΔD (aa 190-252), ΔE (aa 253-315), ΔF (aa 316-378), ΔG (aa 379-439), ΔCT (aa 354-439), T58A S62A and T358A S373A T400A deletions and point mutations were done by PCR.…”

Targeting deubiquitinase activity with a novel small-molecule inhibitor as therapy for B-cell malignancies

“…by guest www.bloodjournal.org From Small-molecule-mediated Usp9x/Usp24 inhibition WP1130 was the first small molecule described with Usp9x inhibitory activity and has shown activity against specific tumors in vitro and in vivo. 9,12,20 However, other DUBs are also WP1130 targets, with some recognized benefits and risks associated with the use of a partially selective DUB inhibitor in a clinical setting. 4 The main limitation for WP1130 as a clinical candidate is its low aqueous solubility (;2.3 mM), which limits its delivery and bioavailability.…”

“…DUB inhibitor WP1130, previously known as Degrasyn, 9 is a partially selective DUB inhibitor shown to inhibit deubiquitinating activity of Usp9x, Usp5, Usp14, and UCH37. 10,11 Usp9x inhibition by WP1130 has been shown to promote apoptosis by reducing Mcl-1 levels and increasing tumor cell sensitivity to chemotherapy.…”

Deubiquitinase Inhibition by Small-Molecule WP1130 Triggers Aggresome Formation and Tumor Cell Apoptosis

“…The antiproliferative and apoptotic effects of WP1130 and less active derivatives (WP1066 and WP1034) against various tumors have recently been reported in chronic myelogenous leukemia (CML; ref. 26), melanoma (27), glioblastoma (28), and myeloproliferative disorders (29). However, unlike AG490, WP1130 did not directly inhibit JAK2 kinase activity, and the mechanism of action of WP1130 remained unclear.…”