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Development of PVTX-405 as a potent and highly selective molecular glue degrader of IKZF2 for cancer immunotherapy

Author

Listed:
  • Zhixiang Chen

    (University of Michigan
    Chinese Academy of Sciences)

  • Harshil Dhruv

    (SK Life Sciences Labs)

  • Xuqing Zhang

    (SK Life Sciences Labs)

  • Rohan Kalyan Rej

    (University of Michigan)

  • Longchuan Bai

    (University of Michigan)

  • Donna McEachern

    (University of Michigan)

  • Paul Kirchhoff

    (University of Michigan)

  • Rakesh Nagilla

    (SK Life Sciences Labs)

  • Larry J. Jolivette

    (SK Life Sciences Labs)

  • Cory T. Rice

    (SK Life Sciences Labs)

  • Peter Orth

    (SK Life Sciences Labs)

  • Corey O. Strickland

    (SK Life Sciences Labs)

  • E. Scott Priestley

    (SK Life Sciences Labs)

  • Helai P. Mohammad

    (SK Life Sciences Labs)

  • Meilin Wang

    (University of Michigan)

  • Bo Wen

    (University of Michigan)

  • Duxin Sun

    (University of Michigan)

  • Zhihua Sui

    (SK Life Sciences Labs)

  • Shaomeng Wang

    (University of Michigan)

Abstract

IKZF2 (Helios) is a transcription factor that is selectively expressed by Tregs and is essential for preserving the function and stability of Tregs in the tumor microenvironment (TME), where it suppresses the anti-tumor immune response. Targeted IKZF2 degradation by small molecules represents a promising strategy for the development of a new class of cancer immunotherapy. Herein, we describe the discovery of PVTX-405, a potent, effective, highly selective, and orally efficacious IKZF2 molecular glue degrader. PVTX-405 degrades IKZF2 (DC50 = 0.7 nM and Dmax = 91%) while sparing other CRBN neo-substrates. Degradation of IKZF2 by PVTX-405 increases production of inflammatory cytokine IL-2 and reduces the suppressive activity of Tregs, leading to an increase in Teff cell proliferation. Once-daily oral administration of PVTX-405 as single agent significantly delays the growth of MC38 tumors in a syngeneic tumor model using humanized CRBN mice. PVTX-405 in combination with anti-PD1 or anti-LAG3 significantly increases animal survival compared to anti-PD1 or anti-LAG3 alone. Together, these results demonstrate that PVTX-405 is a promising IKZF2 degrader for clinical development for the treatment of human cancers.

Suggested Citation

  • Zhixiang Chen & Harshil Dhruv & Xuqing Zhang & Rohan Kalyan Rej & Longchuan Bai & Donna McEachern & Paul Kirchhoff & Rakesh Nagilla & Larry J. Jolivette & Cory T. Rice & Peter Orth & Corey O. Strickla, 2025. "Development of PVTX-405 as a potent and highly selective molecular glue degrader of IKZF2 for cancer immunotherapy," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58431-z
    DOI: 10.1038/s41467-025-58431-z
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    References listed on IDEAS

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    1. Mary E. Matyskiela & Gang Lu & Takumi Ito & Barbra Pagarigan & Chin-Chun Lu & Karen Miller & Wei Fang & Nai-Yu Wang & Derek Nguyen & Jack Houston & Gilles Carmel & Tam Tran & Mariko Riley & Lyn’Al Nos, 2016. "A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase," Nature, Nature, vol. 535(7611), pages 252-257, July.
    2. Jian An & Charles M. Ponthier & Ragna Sack & Jan Seebacher & Michael B. Stadler & Katherine A. Donovan & Eric S. Fischer, 2017. "pSILAC mass spectrometry reveals ZFP91 as IMiD-dependent substrate of the CRL4CRBN ubiquitin ligase," Nature Communications, Nature, vol. 8(1), pages 1-11, August.
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