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Inhibition of cIAP1 as a strategy for targeting c-MYC-driven oncogenic activity

Haoyan Li1,2, Yanjia Fang1, Chunyi Niu1,2

  • 1Interdisciplinary Research Center on Biology and Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 201203 Shanghai, China.

Proceedings of the National Academy of Sciences of the United States of America
|September 6, 2018
PubMed

Insights

Researchers developed a new drug, D19, that inhibits the E3 ubiquitin ligase cIAP1. This drug stabilizes MAD1, leading to the degradation of the cancer-driving protooncogene c-MYC, offering a potential new cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Chemical Biology

Background:

  • The protooncogene c-MYC is a critical driver of human cancers.
  • Targeting c-MYC pharmacologically remains a significant challenge in cancer therapy.
  • E3 ubiquitin ligase cIAP1 regulates c-MYC levels by controlling the stability of its antagonist, MAD1.

Purpose of the Study:

  • To develop a high-throughput assay for cIAP1 ubiquitination.
  • To identify small molecules that inhibit cIAP1 E3 ligase activity.
  • To explore the therapeutic potential of modulating cIAP1 activity for cancer treatment.

Main Methods:

  • Development of a high-throughput assay for cIAP1 ubiquitination.
  • Identification and characterization of D19, a small-molecule inhibitor of cIAP1.
  • Assessment of D19's effects on MAD1 and c-MYC protein levels in cellular and animal models.

Main Results:

  • D19 inhibits cIAP1 E3 ligase activity by binding to its RING domain and interfering with E2 interaction.
  • Inhibition of cIAP1 by D19 stabilizes MAD1, leading to c-MYC degradation and suppression of its oncogenic function.
  • Activating cIAP1 with Smac mimetics destabilizes MAD1 and increases c-MYC levels, demonstrating opposing effects.

Conclusions:

  • Pharmacological inhibition of cIAP1 E3 ligase activity represents a viable strategy for targeting c-MYC in cancer.
  • D19 and its analogs demonstrate potential as anticancer agents by degrading c-MYC.
  • Chemical biological modulation of E3 ubiquitin ligase activity offers distinct therapeutic avenues.
Keywords:
MAD1MYCapoptosiscIAP1ubiquitination

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