PAD4-IN-2 TFA

PAD4-IN-2 TFA is the trifluoroacetate form of PAD4-IN-2 (5i, CAS No.: 2642327-52-2). 5i is a highly targeted inhibitor modified with meta-phenylboronic acid (m-PBA) that takes protein arginine deiminase 4 (PAD4) as the core target. It achieves targeted uptake through the specific binding of m-PBA to sialic acid (SA) on the surface of tumor cells (with no internalization in normal HL7702 cells).

Its core biological functions and key activity values are as follows: In vitro, it exhibits an inhibitory activity against PAD4 with an IC₅₀ of 1.94±0.65 μM and no direct tumor cell-killing activity (no significant effect on 4T1 cell viability at a concentration of 100 μM). However, it can dose-dependently inhibit the clonal proliferation and migration of 4T1 cells (the migration inhibitory effect at 100 μM is superior to that of the positive control RGDS). Meanwhile, it can reduce the level of histone H3 citrullination (H3cit) in the cytoplasm of tumor cells and the nucleus of neutrophils, and significantly decrease the formation of neutrophil extracellular traps (NETs); In vivo, at a dose of 10 μmol/kg, it achieves a tumor inhibition rate of 49.2% against S180 sarcoma. In the 4T1 breast cancer model, it dose-dependently inhibits the growth of primary tumors and lung metastasis, and can regulate the tumor immune microenvironment (increasing the proportion of normal neutrophils and M1 macrophages, and reducing aged neutrophils Naged CD194hi|CD62Llo).

In terms of safety, its serum indices including creatinine (Cr), blood urea nitrogen (BUN), aspartate transaminase (AST), and alanine transaminase (ALT) show no difference from those of the normal group, with no obvious hepatotoxicity or nephrotoxicity, which is superior to the control drug YW3-56 (CAS No.: 1374311-17-7).

References:

[1] Zhu D, Lu Y, Hu B, Pang Y, Liu B, Zhang M, Wang W, Wang Y. Highly-tumor-targeted PAD4 inhibitors with PBA modification inhibit tumors in vivo by specifically inhibiting the PAD4-H3cit-NETs pathway in neutrophils. Eur J Med Chem. 2023 Oct 5;258:115619. doi: 10.1016/j.ejmech.2023.115619. Epub 2023 Jul 3. PMID: 37421890.