Development of PVTX-405 as a potent and highly selective molecular glue degrader of IKZF2 for cancer immunotherapy.
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ID: 281579
2025
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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 (DC = 0.7 nM and D = 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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chen2025development
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| Authors | Chen, Zhixiang; Dhruv, Harshil; Zhang, Xuqing; Rej, Rohan Kalyan; Bai, Longchuan; McEachern, Donna; Kirchhoff, Paul; Nagilla, Rakesh; Jolivette, Larry J; Rice, Cory T; Orth, Peter; Strickland, Corey O; Priestley, E Scott; Mohammad, Helai P; Wang, Meilin; Wen, Bo; Sun, Duxin; Sui, Zhihua; Wang, Shaomeng |
| Journal | Nature communications |
| Year | 2025 |
| DOI |
10.1038/s41467-025-58431-z
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| URL | |
| Keywords | Keywords not found |
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