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Updated: Jan 11, 2026

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Catalytic Inhibition of p300 Preferentially Targets IRF4 Oncogenic Activity and Tumor Growth in Multiple Myeloma

W Frank Lenoir1, Michael R McKeown1, Giulia Giorgetti2

  • 1Kronos Bio, Cambridge, Massachusetts.

Cancer Research
|November 17, 2025
PubMed

Insights

Researchers identified p300 as a key partner of the oncogenic transcription factor IRF4 in multiple myeloma (MM). Inhibiting p300 (a KAT enzyme) effectively targets MM cells, showing promise for new MM therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • The transcription factor IRF4 is crucial for multiple myeloma (MM) survival but remains undrugged.
  • Identifying key partners of IRF4 is essential for developing targeted MM therapies.

Purpose of the Study:

  • To identify IRF4 partners using transcriptional regulatory network (TRN) mapping.
  • To evaluate p300/CBP lysine acetyltransferase (KAT) inhibitors as a therapeutic strategy for MM.

Main Methods:

  • Transcriptional regulatory network (TRN) mapping and quantitative interactome mapping were employed.
  • p300/CBP KAT inhibitors were developed and tested for their ability to inhibit IRF4 activity and MM proliferation.
  • Comparative analysis with existing p300/CBP bromodomain inhibitors was performed.

Main Results:

  • p300 was identified as a key IRF4 partner, with IRF4 being a highly abundant MM-specific dependency.
  • p300/CBP KAT inhibition effectively suppressed IRF4 activity and MM cell proliferation both ex vivo and in vivo.
  • KAT inhibitors demonstrated preferential targeting of MM cells and superior inhibition of IRF4 compared to bromodomain inhibitors.
  • Combination therapy with KAT inhibitors and other MM therapeutics showed synergistic anti-tumor effects.

Conclusions:

  • p300 is a critical coactivator for IRF4 in MM, making it a viable therapeutic target.
  • p300/CBP KAT inhibition represents a promising strategy for MM treatment, particularly in combination therapies.
  • Ongoing clinical development of p300/CBP KAT inhibitors is warranted for MM.

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