A small molecule inhibitor of NVL suppresses tumor growth by blocking ribosome biogenesis

Area of Science:

• Molecular Biology
• Oncology
• Drug Discovery

Background:

• Ribosome biogenesis is upregulated in cancer cells, presenting a potential therapeutic vulnerability.
• Existing chemotherapies can disrupt ribosome production, but selective inhibitors are needed.

Purpose of the Study:

• To identify novel therapeutic targets within the ribosome biogenesis pathway.
• To investigate the mechanism of action for MM17, a dibenzothiazepinone anticancer agent.
• To evaluate the therapeutic potential of NVL inhibitors in preclinical cancer models.

Main Methods:

• Forward genetics screen to identify resistance mutations to MM17.
• Cryo-electron microscopy (Cryo-EM) to determine the structure of the NVL-MM17 complex.
• Assessment of MM17's effects on ribosome biogenesis, cell cycle, and apoptosis.
• Preclinical studies of MM927 in mouse models of leukemia and colorectal cancer.

Main Results:

• Mutations in the 60S ribosomal subunit assembly factor NVL conferred resistance to MM17.
• Cryo-EM revealed MM17 binding sites on NVL adjacent to resistance mutations.
• MM17 inhibited 60S ribosome biogenesis, inducing p53-dependent and -independent cell death without DNA damage.
• The analog MM927 demonstrated efficacy in suppressing tumor growth in vivo with no observed toxicity.

Conclusions:

• NVL is a validated target for cancer therapy.
• Inhibitors of ribosome biogenesis, such as NVL inhibitors, represent a promising new class of targeted therapeutics.
• Targeting ribosome production exploits a cancer-specific vulnerability for effective treatment.