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<p>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 (DC<sub>50</sub> = 0.7 nM and D<sub>max</sub> = 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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年5月1日

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  • 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. Strickland,
  • E. Scott Priestley,
  • Helai P. Mohammad,
  • Meilin Wang,
  • Bo Wen,
  • Duxin Sun,
  • Zhihua Sui,
  • Shaomeng Wang

摘要

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.