Improved low molecular weight Myc-Max inhibitors

Abstract

Compounds that selectively prevent or disrupt the association between the c-Myc oncoprotein and its obligate heterodimeric partner Max (Myc-Max compounds) have been identified previously by high-throughput screening of chemical libraries. Although these agents specifically inhibit the growth of c-Myc -expressing cells, their clinical applicability is limited by their low potency. We describe here several chemical modifications of one of these original compounds, 10058-F4, which result in significant improvements in efficacy. Compared with the parent structure, these analogues show enhanced growth inhibition of c-Myc -expressing cells in a manner that generally correlates with their ability to disrupt c-Myc-Max association and DNA binding. Furthermore, we show by use of a sensitive fluorescence polarization assay that both 10058-F4 and its active analogues bind specifically to monomeric cMyc. These studies show that improved Myc-Max compounds can be generated by a directed approach involving deliberate modification of an index compound. They further show that the compounds specifically target c-Myc, which exists in a dynamic and relatively unstructured state with only partial and transient A-helical content. [Mol Cancer Ther 2007;6(9):2399 -408]

Efficacy, pharmacokinetics, tisssue distribution, and metabolism of the Myc–Max disruptor, 10058-F4 [Z,E]-5-[4-ethylbenzylidine]-2-thioxothiazolidin-4-one, in mice

“…Similar inhibition was observed in HepG2 cells after exposure to 100 μM 10058-F4 for 24 h [8]. While our study was in progress, Wang et al [24] examined structural analogs of 10058-F4 and found that one analog was about twofold more potent than 10058-F4 in inhibiting the growth of HL-60 cells in vitro; the IC 50 of 27HR was 23 μM compared to 51 μM for 10058-F4. As an initial attempt to evaluate the therapeutic potential of 10058-F4, we evaluated the pharmacological properties, including the efficacy of 10058-F4 in mice.…”

“…Thus, as the quest for new small molecule inhibitors of c-Myc/Max continues, attention should be paid not only to in vitro potency, but also to less metabolically labile compounds. Newer analogs [24] hopefully will have improved pharmacokinetic features. 12.60…”

The Quassinoid Derivative NBT-272 Targets Both the AKT and ERK Signaling Pathways in Embryonal Tumors

“…Two small-molecule inhibitors specifically targeting the MYC/Max interaction (34,35) did not show the same profile of activity as NBT-272 (Fig. 4C).…”

“…Indeed, we could observe that inhibition of the proteasome-dependent protein degradation pathway restored the depleting effect of NBT-272 and almost completely stabilized c-MYC. Moreover, the effect induced by 2 specific MYC/Max inhibitors (34,35) and by c-MYC silencing in ET cells did not match the cellular response to NBT-272, again detrimental to the hypothesis of a direct effect on MYC. This conclusion, however, certainly does not exclude that MYC inhibition contributed to the panel of cellular responses observed on NBT-272 treatment.…”

Embryonal neural tumours and cell death

“…One molecule, 10058-F4, has been extensively studied and found to induce cell cycle arrest, apoptosis, and differentiation in some cells in addition to its disruption of Myc/Max [151,152]. However, the relatively low potencies of the identified Myc/Max compounds called for attempts to improve their efficacy, a challenge that was taken on by Prochownik et al They have chemically modified 10058-F4 to generate analogues with improved efficacy that are better suitable for in vivo treatment [153]. By this approach, they showed that 10058-F4 and its analogues bind directly to monomeric Myc, which may be important in design of even more potent compounds in the future.…”