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 D. Kirchhoff, Rakesh Nagilla, Larry J. Jolivette, Cory Rice, Peter Orth, Corey O. Strickland, E. Scott Priestley, Helai P. Mohammad, Meilin Wang, Bo Wen, Duxin Sun, Zhihua Sui, Shaomeng Wang
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. Targeted IKZF2 degradation represents a potential therapeutic strategy for cancer immunotherapy. Here, the authors described the discovery of PVTX-405 as a potent, highly selective, and orally efficacious IKZF2 molecular glue degrader and their preclinical data support the clinical development of PVTX-405.