9DOM
PVTX-405: A Potent, Highly Selective, and Orally Efficacious Molecular Glue Degrader of IKZF2 for Cancer Immunotherapy
This is a non-PDB format compatible entry.
Summary for 9DOM
| Entry DOI | 10.2210/pdb9dom/pdb |
| Descriptor | Protein cereblon, Zinc finger protein Helios, (3S)-3-(1'-benzyl-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione, ... (5 entities in total) |
| Functional Keywords | molecular glue protein degrader, transcription |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 8 |
| Total formula weight | 64744.58 |
| Authors | |
| Primary citation | Chen, Z.,Dhruv, H.,Zhang, X.,Rej, R.K.,Bai, L.,McEachern, D.,Kirchhoff, P.,Nagilla, R.,Jolivette, L.J.,Rice, C.T.,Orth, P.,Strickland, C.O.,Priestley, E.S.,Mohammad, H.P.,Wang, M.,Wen, B.,Sun, D.,Sui, Z.,Wang, S. Development of PVTX-405 as a potent and highly selective molecular glue degrader of IKZF2 for cancer immunotherapy. Nat Commun, 16:4095-4095, 2025 Cited by PubMed 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. PubMed: 40312344DOI: 10.1038/s41467-025-58431-z PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.69 Å) |
Structure validation
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