Small-molecule inhibitors of c-Myc transcriptional factor suppress proliferation and induce apoptosis of promyelocytic leukemia cell via cell cycle arrest

Abstract

c-Myc plays a decisive role in the proliferation of HL-60 promyelocytic leukemia cells. In the present study, we demonstrated that an inhibitor of c-Myc/Max/DNA complex formation has a high potentiality as a suppressor of c-Myc-involved cell signaling. We prepared recombinant c-Myc and Max proteins encompassing the human-origin DNA binding and dimerization domains, and tested a chemical library of 6480 small molecules for their inhibitory effect on the in vitro formation of the c-Myc/Max/DNA complex as well as their influence on DMSO-differentiated HL-60 cells. We found several hit compounds through in vitro and cell-based screening tests, and also confirmed these compounds significantly inhibited the formation of the recombinant c-Myc/Max/DNA complex in the low micromolar range. Indeed, these inhibitors effectively blocked c-Myc-associated gene expression in cancer cell line, suppressed the proliferation and induced the apoptosis of HL-60 promyelocytic leukemia cells via cell cycle arrest without altering the expression level of c-Myc in the DMSO-differentiated HL-60 cells. These successive results suggest that our c-Myc/Max/DNA complex inhibitors potently contribute to the suppression of the Myc-dependent proliferation of leukemia cells and to the induction of apoptosis. Accordingly, we would expect that these compounds could serve as lead compounds in the development of novel anticancer drugs.

8-Chloroadenosine 3′,5′-monophosphate induces cell cycle arrest and apoptosis in multiple myeloma cells through multiple mechanisms

“…It has been previously reported that small-molecule inhibitors of c-myc suppress proliferation and induce apoptosis of promyelocytic leukemia cells via cell cycle arrest (39,40). Although our data show that 8-Cl-cAMP induced the downregulation of c-myc, the mechanism for this action is not well defined.…”

BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc

“…To date, efforts to target c-Myc have identified only a small number of molecules with low biochemical potency and limited biological characterization (Bidwell et al, 2009; Hammoudeh et al, 2009; Jeong et al, 2010), underscoring both the challenge of targeting c-Myc as well as the enduring need for chemical probes of c-Myc transcriptional function. Considering chromatin as a platform for signal transduction (Schreiber and Bernstein, 2002), we have undertaken to inhibit Myc transcription and function through displacement of chromatin-bound, co-activator proteins using competitive small molecules.…”

Targeting disordered proteins with small molecules using entropy

“…As is the case with c-Myc described earlier, drugs that target disordered regions have shown promising initial results both in vitro and in vivo, and more metabolically stable analogues are currently in development [6,22,52]. An ability to modify the behaviour of disordered proteins via the use of small molecules may have profound implications for disease.…”