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<p>The MAX (MYC-associated protein X) was discovered as an obligate heterodimer of MYC, a protein product of a prolific proto-oncogene that is dysregulated in over three-fourths of cancers. Targeting MYC directly is fraught with challenges due to the disordered structure of the MYC protein that is not conducive for small molecule inhibitor design. Therefore, the MYC/MAX protein–protein interaction provides an opportunity for indirect targeting of MYC. We compared the efficacy of first- and second-generation MYC/MAX small molecular inhibitors, 10,058-F4 and 3jc48-3 respectively, and tested the novel class of proteomimetic MYC/MAX inhibitor JKY-2–169 on inhibiting growth of human prostate cancer cell line DU145 in 2D culture. In addition, we validated the efficacy of inhibitors using 3-dimensional (3D) systems: 3D microcapsules and human prostate cancer spheroids generated by harvesting fresh cancerous tissue from human radical prostatectomy surgical specimens. Treatment in both 3D models showed that 3jc48-3 and JKY-2–169 reduced cell viability. Analysis of patient-derived spheroids before and after treatment showed that spheroid growth increased significantly over time only in the DMSO control group, while inhibitor-treated spheroids did not show significant growth during the same period; among the treatment groups, only 3jc48-3 significantly reduced spheroid size compared with the DMSO control. The results suggest that the proteomimetic and second-generation MYC inhibitors suppress cell growth at lower concentrations compared to the first-generation inhibitors. Comparative proteomic analysis of treated and untreated DU145 cells, based on a pre-defined twofold expression threshold, identified common cellular pathways altered by MYC/MAX inhibition primarily involving cytoskeletal organizations, cell cycle regulation, metabolism, and RNA-related functions. This study provides promising preliminary in vitro support for further investigation and development of novel MYC inhibitors.</p>

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Prostate cancer cells’ growth is decreased by novel MYC inhibitors 

  • 期刊论文

  • 发表日期：

    2026年4月28日

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  • Bita Nickkholgh,
  • Joseph McGrath,
  • Sivanandane Sittadjody,
  • Jay Chauhan,
  • Kwan-Young Jung,
  • Steven Fletcher,
  • K. C. Balaji

摘要

The MAX (MYC-associated protein X) was discovered as an obligate heterodimer of MYC, a protein product of a prolific proto-oncogene that is dysregulated in over three-fourths of cancers. Targeting MYC directly is fraught with challenges due to the disordered structure of the MYC protein that is not conducive for small molecule inhibitor design. Therefore, the MYC/MAX protein–protein interaction provides an opportunity for indirect targeting of MYC. We compared the efficacy of first- and second-generation MYC/MAX small molecular inhibitors, 10,058-F4 and 3jc48-3 respectively, and tested the novel class of proteomimetic MYC/MAX inhibitor JKY-2–169 on inhibiting growth of human prostate cancer cell line DU145 in 2D culture. In addition, we validated the efficacy of inhibitors using 3-dimensional (3D) systems: 3D microcapsules and human prostate cancer spheroids generated by harvesting fresh cancerous tissue from human radical prostatectomy surgical specimens. Treatment in both 3D models showed that 3jc48-3 and JKY-2–169 reduced cell viability. Analysis of patient-derived spheroids before and after treatment showed that spheroid growth increased significantly over time only in the DMSO control group, while inhibitor-treated spheroids did not show significant growth during the same period; among the treatment groups, only 3jc48-3 significantly reduced spheroid size compared with the DMSO control. The results suggest that the proteomimetic and second-generation MYC inhibitors suppress cell growth at lower concentrations compared to the first-generation inhibitors. Comparative proteomic analysis of treated and untreated DU145 cells, based on a pre-defined twofold expression threshold, identified common cellular pathways altered by MYC/MAX inhibition primarily involving cytoskeletal organizations, cell cycle regulation, metabolism, and RNA-related functions. This study provides promising preliminary in vitro support for further investigation and development of novel MYC inhibitors.