Anticancer agent 82

Anticancer agent 82 is a FiVe1 derivative, an orally active and selective anticancer agent. FiVe1 binds type III intermediate filament protein vimentin (VIM), to induce hyperphosphorylation of Ser56, resulting selective disruption of mitosis and multinucleation in transformed VIM-expressing mesenchymal cancer cells. Anticancer agent 82 shows better oral bioavailability and pharmacokinetic profiles than FiVe1[1].

Research Areas >> Cancer

Signaling Pathways >> Metabolic Enzyme/Protease >> Proteasome

vimentin (VIM)[1]

Anticancer agent 82 (compound 4e) (0-10 mM; 72 h) inhibits a marked improvement in potency with an IC50 value of 44 nM against HT-1080 fibrosarcoma, better than than FiVe1 (IC50=1.6 μM, HT-1080)[1]. Anticancer agent 82 (0.1 μM; 24 h) induces phosphorylation of VIM at Ser56[1]. Anticancer agent 82 (100 μM; sampled at 0, 5, 15, 30, 45, and 60 min) exhibits poor stability with 0.0% remaining after 60 min of incubation in mouse liver microsome[1]. Cell Viability Assay[1] Cell Line: HT-1080, RD, and MCF-7 cells Concentration: 0-10 mM Incubation Time: 72 hours Result: Inhibited HT-1080, RD, and MCF-7 cells with IC50s of 44 nM, 61 nM, and 49 nM, respectively.

Anticancer agent 82 (compound 4e) (10 mg/kg; p.o.; single dose) shows better oral pharmacokinetic properties than Five1[1]. Pharmacokinetic properties of Anticancer agent 82 in mice[1] Route Dose (mg/kg) AUC0-last (ng·h/mL) AUC0-inf (ng·h/mL) T1/2 (h) Tmax (h) Tlast (h) Cmax (ng/mL) 4e PO 10 371.33 534.33 4.68 0.67 8 154.67 4e IP 1 208.33 211.33 0.59 0.25 4 197.00 Five1 PO 25 309.78 339.21 4.57 0.5 18 110.43

[1]. Martínez-Peña F, et al. Synthesis and biological evaluation of novel FiVe1 derivatives as potent and selective agents for the treatment of mesenchymal cancers. Eur J Med Chem. 2022 Nov 15;242:114638.