ALV2 is an effective and selective degrader of Helios (IKZF2). ALV2 binds to CRBN with an IC50 of 0.57μM[1-2]. Helios is a zinc-finger transcription factor that maintains a stable regulatory T cell (Treg) phenotype within the inflammatory tumor microenvironment. ALV2 is used in research investigating the regulation of T cell function and the tumor immune microenvironment[3-4].
In vitro, ALV2 (1μM) was used to pre-treat human naive CD4+ T cells for 5 days, followed by activation with anti-CD3/CD28 antibodies for 2 days. This treatment significantly upregulated the production of CD25 and effector cytokines (such as IL-21 and IFNγ), and enhanced the ability of these cells to infiltrate inflammatory tissues in a human-synovial tissue-mouse chimeric model[5]. In RAW 264.7 murine macrophages infected with Salmonella for 1 hour, ALV2 (10μM; 24-hour treatment) significantly reduced the secretion of tumor necrosis factor-alpha (TNF-α)[6].
In vivo, in a mouse model with the humanized CrbnI391Vgenotype, administration of ALV2 via intraperitoneal injection (100mg/kg; twice daily; for 7 days) significantly reduced the protein levels of Helios (IKZF2) in splenic CD4+ FoxP3+ regulatory T cells (Tregs), without affecting Ikaros (IKZF1) levels[7].
References:
[1] Zhang Y, Li L, Xu J, et al. A Novel Paradigm for Targeting Challenging Targets: Advancing Technologies and Future Directions of Molecular Glue Degraders. Molecules (Basel, Switzerland). 2026 Jan;31(3):459.
[2] Słabicki M, Park J, Nowak RP, et al. Expanding the druggable zinc-finger proteome defines properties of drug-induced degradation. Molecular Cell. 2025 Aug;85(16):3184-3201.e14.
[3] Xue F, Zhang M, Li S, et al. SE(3)-equivariant ternary complex prediction towards target protein degradation. Nature Communications. 2025 Jul;16(1):5514.
[4] Chen Z, Dhruv H, Zhang X, et al. Development of PVTX-405 as a potent and highly selective molecular glue degrader of IKZF2 for cancer immunotherapy. Nature Communications. 2025 May;16(1):4095.
[5] Zhang H, Jadhav RR, Cao W, et al. Aging-associated HELIOS deficiency in naive CD4+ T cells alters chromatin remodeling and promotes effector cell responses. Nat Immunol. 2023 Jan;24(1):96-109.
[6] Santelices J, Schultz A, Walker A, et al. Targeting deubiquitinating enzymes and ubiquitin pathway modulators to enhance host defense against bacterial infections. mBio. 2025 Oct 8;16(10):e0031225.
[7] Wang ES, Verano AL, Nowak RP, et al. Acute pharmacological degradation of Helios destabilizes regulatory T cells. Nat Chem Biol. 2021 Jun;17(6):711-717.