3JC48-3 (methyl 4'-methyl-5-(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)-[1,1'-biphenyl]-3-carboxylate): a novel MYC/MAX dimerization inhibitor reduces prostate cancer growth.

Abstract

The proto-oncogene cellular myelocytomatosis (c-Myc) is a transcription factor that is upregulated in several human cancers. Therapeutic targeting of c-Myc remains a challenge because of a disordered protein tertiary structure. The basic helical structure and zipper protein of c-Myc forms an obligate heterodimer with its partner MYC-associated factor X (MAX) to function as a transcription factor. An attractive strategy is to inhibit MYC/MAX dimerization to decrease c-Myc transcriptional function. Several methods have been described to inhibit MYC/MAX dimerization including small molecular inhibitors and proteomimetics. We studied the effect of a second-generation small molecular inhibitor 3JC48-3 on prostate cancer growth and viability. In our experimental studies, we found 3JC48-3 decreases prostate cancer cells' growth and viability in a dose-dependent fashion in vitro. We confirmed inhibition of MYC/MAX dimerization by 3JC48-3 using immunoprecipitation experiments. We have previously shown that the MYC/MAX heterodimer is a transcriptional repressor of a novel kinase protein kinase D1 (PrKD1). Treatment with 3JC48-3 upregulated PrKD1 expression and phosphorylation of known PrKD1 substrates: the threonine 120 (Thr-120) residue in beta-catenin and the serine 216 (Ser-216) in Cell Division Cycle 25 (CDC25C). The mining of gene expression in human metastatic prostate cancer samples demonstrated an inverse correlation between PrKD1 and c-Myc expression. Normal mice and mice with patient-derived prostate cancer xenografts (PDX) tolerated intraperitoneal injections of 3JC48-3 up to 100 mg/kg body weight without dose-limiting toxicity. Preliminary results in these PDX mouse models suggest that 3JC48-3 may be effective in decreasing the rate of tumor growth. In conclusion, our study demonstrates that 3JC48-3 is a potent MYC/MAX heterodimerization inhibitor that decreases prostate cancer growth and viability associated with upregulation of PrKD1 expression and kinase activity.

• Authors: Sanjeev Shukla, Steven Fletcher, Jay Chauhan, Victor Chalfant, Carlos Riveros, Yuri Mackeyev, Pankaj Kumar Singh, Sunil Krishnan, Teruko Osumi, K C Balaji
• Journal: Cancer gene therapy (Cancer Gene Ther) Vol. 29 Issue 11 Pg. 1550-1557 (11 2022) ISSN: 1476-5500 [Electronic] England
• PMID: 35440696 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Chemical References

• diphenyl
• Proto-Oncogene Proteins c-myc
• Transcription Factors
• Carboxylic Acids

Topics

• Humans
• Male
• Mice
• Animals
• Dimerization
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• Prostatic Neoplasms (drug therapy, genetics)
• Transcription Factors (metabolism)
• Carboxylic Acids