Small molecule inhibitors targeting the respective enzyme pockets or acetylated histone binding surfaces have all shown some efficacies against MYC, with BET inhibitors being the most well-studied 6, 7, 8, 9, 10, 11. Epigenetic targets include histone deacetylase, acetylase, demethylase, methylase, and bromodomain and extra-terminal motif (BET) proteins. In addition to directly targeting MYC, the epigenetic silencing of MYC gene expression by targeting histone modifying enzymes or binding proteins also reduces MYC expression. As expected, Omomyc inhibits the cell growth of multiple cancer cell types in vitro and in vivo 5.
Four mutations in the leucine zipper region still permit Omomyc to dimerize with all MYC family proteins, but effectively prevent the MYC/MAX heterodimers from binding their target promoters thereby inhibiting MYC-dependent gene expression 5. Omomyc is a MYC-specific inhibitor, which is a miniprotein 90 amino acids in length derived from the MYC basic helix-loop-helix (bHLH) domain that acts as a dominant negative mutant for the MYC dimerization domain 4. Nonetheless, several MYC-specific inhibitors have been developed successfully.
However, MYC, like other transcription factors, possesses a highly disordered structure, which facilitates interaction with multiple cofactors and DNA 2, 3, but hampers development of specific small molecule inhibitors.
Rta com driver#
The ubiquitous nature of MYC deregulation in most types of cancers and its inherent driver function for cell proliferation make MYC a very attractive target for cancer drug development. Mechanistically, increased MYC protein concentration in the nucleus facilitates its interaction with E-box transcription factors, which triggers tumorigenesis by promoting cell proliferation in contrast, these events should not occur in resting cells with tightly regulated, normal physiological levels of MYC. Numerous studies suggest that deregulation of MYC expression occurs in >70% of cancers overall and contributes to disease progression, metastatic potential, and therapeutic resistance 1. This study thus provides a unique tool to control MYC activation, which may be used as a therapeutic payload to treat MYC-dependent diseases such as cancers and autoimmune diseases.Įxpression of c-Myc ( MYC) is tightly regulated in normal cells but becomes dysregulated and often over-expressed in many types of human cancer cells. Thiol(SH)-linked alkylation for the metabolic sequencing of RNA ( SLAM seq) with target-transcriptional analyses further confirm that the viral peptide directly attenuates MYC and MYC-target gene expression. Mechanistically, the peptide functions as a decoy to block the recruitment of coactivator complexes consisting of Nuclear receptor coactivator 2 (NCOA2), p300, and SWI/SNF proteins to the MYC promoter in primary effusion lymphoma cells. Here, we show a small peptide derived from the Kaposi’s sarcoma-associated herpesvirus transactivator (K-Rta) sequence, which attenuates cellular MYC expression, reduces cell proliferation, and selectively kills cancer cell lines in both tissue culture and a xenograft tumor mouse model.
In herpesvirus replicating cells, host cell gene transcription is frequently down-regulated because important transcriptional apparatuses are appropriated by viral transcription factors.
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