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

  • Nat Commun. 2025 May 1;16(1):4095. doi: 10.1038/s41467-025-58431-z.
Zhixiang Chen  #  1  2 ,  Harshil Dhruv  #  3 ,  Xuqing Zhang  #  3 ,  Rohan Kalyan Rej  #  1 ,  Longchuan Bai  #  1 ,  Donna McEachern  1 ,  Paul Kirchhoff  1 ,  Rakesh Nagilla  3 ,  Larry J Jolivette  3 ,  Cory T Rice  3 ,  Peter Orth  3 ,  Corey O Strickland  3 ,  E Scott Priestley  3 ,  Helai P Mohammad  3 ,  Meilin Wang  4 ,  Bo Wen  4 ,  Duxin Sun  4 ,  Zhihua Sui  3 ,  Shaomeng Wang  5
Affiliations
  • 1. Rogel Cancer Center, Department of Internal Medicine, Department of Pharmacology, and, Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA.
  • 2. Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
  • 3. SK Life Sciences Labs, King of Prussia, PA, USA.
  • 4. Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA.
  • 5. Rogel Cancer Center, Department of Internal Medicine, Department of Pharmacology, and, Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA. [email protected].
  • # Contributed equally.
PMID: 40312344 DOI: 10.1038/s41467-025-58431-z
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.

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