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excellent pre-clinical efficacy in Myc-dependent tumor models and are currently in clinical trials. Several groups have also reported small molecule inhibitors that bind directly to Myc and inhibit its interaction with Max . These inhibitors, originally introduced by Prochownik et al, bind with micromolar affinity and disrupt the Myc:Max interaction, as well as inhibit proliferation of PI-103 customer reviews Myc-expressing tumor cell lines. Two such small molecules, 10058-F5 and 10074-G5, have been shown to bind independently and simultaneously to the disordered conformation of the basic helix-loop-helix leucine zipper domain of Myc, thus inhibiting its interaction with Max . Additionally, close analogs of 10058-F4 and 10074-G5 with similar and improved potencies have been described . We have utilized our technology platform to develop self-assembling dimeric inhibitors of Myc using these previously described small molecules as our starting individual ligands. These molecules are additionally modified with appended connectors and linkers designed to facilitate reversible dimer formation. We demonstrate that our new inhibitors directly bind to Myc with improved affinity over the existing small molecule inhibitors, disrupt the Myc:Max interaction in vitro, and impact expression of MYC regulated genes in cells resulting in anti-proliferative effects in Myc-expressing tumor cell lines. K562 , Daudi , Raji and MV4-11 cells were purchased directly from American Type Culture Collection and routinely cultured under recommended conditions. Growth and proliferation was determined by use of Cell Titer 96 Aqueous One Eliglustat (hemitartrate) Solution . All cells were plated at 10,000 cells per well in growth media in a clear 96 well plate. After 3 days of compound treatment reagent was added, and absorbance at 490 nm was read after incubation for 4 hours at 37. A control plate of compound diluted in media at the same concentrations was treated in a similar way and these values subtracted from the cell plate data to control for any compound interference in the assay. Synergy was determined using the Bliss model of independence. Drug treated cells were washed in PBS and lysed in RIPA buffer on ice for 30 minutes. Total p

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Author: calcimimeticagent