Development of PVTX-405 as a potent and highly selective molecular glue degrader of IKZF2 for cancer immunotherapy
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.
Authors
- Larry J. Jolivette
- Bo Wen (ORCID: https://orcid.org/0000-0003-2261-3150)
- Meilin Wang (ORCID: https://orcid.org/0000-0003-4509-9561)
- Harshil Dhruv (ORCID: https://orcid.org/0000-0003-2571-6649)
- Rakesh Nagilla
- Cory Rice (ORCID: https://orcid.org/0000-0003-2270-030X)
- Rohan Kalyan Rej (ORCID: https://orcid.org/0000-0003-0904-9137)
- E. Scott Priestley (ORCID: https://orcid.org/0000-0001-8390-1143)
- Longchuan Bai (ORCID: https://orcid.org/0000-0003-1025-2925)
- Donna McEachern (ORCID: https://orcid.org/0000-0001-8662-3425)
- Peter Orth (ORCID: https://orcid.org/0000-0002-8475-682X)
- Duxin Sun (ORCID: https://orcid.org/0000-0002-6406-2126)
- Paul D. Kirchhoff (ORCID: https://orcid.org/0000-0002-0309-2612)
- Shaomeng Wang (ORCID: https://orcid.org/0000-0002-8782-6950)
- Xuqing Zhang (ORCID: https://orcid.org/0000-0001-8996-2908)
- Zhixiang Chen (ORCID: https://orcid.org/0009-0007-4526-1588)
- Corey O. Strickland
- Zhihua Sui
- Helai P. Mohammad
Institutions
- Chinese Academy of Sciences (CN)
- University of Michigan (US)
- Shanghai Institute of Organic Chemistry (CN)
- Michigan Medicine (US)
- SK Life Science (United States) (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-01
- DOI
- https://doi.org/10.1038/s41467-025-58431-z
- Citations
- 12
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 9.67
Funders
- National Institutes of Health
- University of Michigan Comprehensive Cancer Center
- National Cancer Institute