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

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 and Shaomeng Wang ()
Additional contact information
Zhixiang Chen: University of Michigan
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

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58431-z

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