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December 8, 2025BloodOpen Access

Novel multifunctional degraders of EP300/CBP and IKZF1/3 with potent anti-myeloma activity

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Authors

DADalya AtacaBMBernice MatusowGBGideon Bollag

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Overview

In preclinical models, polypharmacology approach using OPN-5877 reduces IRF4 expression and inhibits myeloma growth.

Key Points

  • To evaluate the effectiveness of multifunctional chimeras targeting EP300, CBP, IKZF1, and IKZF3 in multiple myeloma.
  • Synthesis of over 200 chimeric compounds
  • Functional assays characterized individual compounds
  • Screening for degradation using HiBiT technology
  • Western blotting validated target protein levels
  • Cell proliferation assays assessed anti-cancer activity.
  • OPN-5667 achieved 117% tumor growth inhibition in OPM-2 xenografts
  • OPN-5877 showed improved DC50 preferentially targeting all four proteins
  • IC50 values indicated strong anti-proliferative effects in myeloma cell lines
  • Reduction of IRF4 expression correlated with treatment efficacy.

Cite This Study

Ataca et al. (2025) studied this question.

synapsesocial.com/papers/69362f514fa91c937236d955https://doi.org/10.1182/blood-2025-573
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