DEL-22379

DEL-22379 is an ERK dimerization Inhibitor. DEL-22379 readily binds to ERK2 with a K_d estimated in the low micromolar range, though binding is detectable even at low nanomolar concentrations. ERK2 dimerization is progressively inhibited with an IC₅₀ of ~0.5 μM. IC50 & Target: IC50: ~0.5 μM (ERK2 dimerization)^[1] In Vitro: DEL-22379 is an ERK dimerization inhibitor. DEL-22379 abolishes EGF-induced co-immunoprecipitation of ectopic ERK2 molecules tagged with hemagglutinin (HA) or FLAG epitopes, with an estimated half-maximal inhibitory concentration (IC₅₀) of ~0.5 μM. DEL-22379 inhibits growth of tumor cells harboring RAS-ERK pathway oncogenes. The biological effects of DEL-22379 are investigated on tumor cells in culture. The cytostatic effects of DEL-22379 are compared to those of the MEK inhibitor PD-0325901 and the ERK kinase inhibitor SCH-772984, as reflected by their half-maximal growth inhibitory concentrations (GI₅₀). Cell lines harboring mutant BRAF are the most sensitive to the three compounds. In comparison, wild-type (WT) cell lines for BRAF and RAS are the most resistant, and RAS mutant cells exhibit a range of sensitivities. In cells showing different oncogenic genotypes, distinct sensitivity to DEL-22379 can not be attributed to variations on its effects on dimerization, because DEL-22379 displays similar dimerization- and cytoplasmic signaling-inhibitory dose responses (IC₅₀ of 150-400 nM) regardless of the genotype^[1]. In Vivo: To test DEL-22379 antitumor effects, some of the aforementioned cell lines are xenografted into nude mice, and tumor growth is monitored after intra-peritoneal administration of DEL-22379 at 15 mg/kg. At such a dose, inhibition of ERK dimerization is evident in liver extracts and in xenografted tumors. DEL-22379 markedly inhibits tumor progression for A375 cells (BRAF mutant)^[1].