E6201 (ER-806201) is a potent dual kinase inhibitor targeting MEK1 and FLT3, inhibiting their activities in an ATP-competitive manner. It effectively suppresses MEK1-induced ERK2 phosphorylation (IC50 = 5.2 nM), MKK4-induced JNK phosphorylation (IC50 = 91 nM), and MKK6-induced p38 MAPK phosphorylation (IC50 = 19 nM). E6201 exhibits anti-tumor and anti-psoriasis effects [1] [2].

E6201 is an inhibitor of MEKK1 and MEK families but not the MAPK family. E6201 inhibits MEKK1- induced phosphorylation of MEK1, MKK4, and MKK6 with IC 50 values of 31, 522, and 65 nM, respectively. E6201 has no effect on other MAPK family enzymes such as ERK2, JNKs, and p38 MAPK at 10 μM [1]. E6201 inhibits LPS-induced TNF transcription with an IC 50 value of 50±14 nM, but does not suppress β-actin transcription at 3 μM and only slightly at 10 μM [1]. E6201 inhibits the receptor tyrosine kinases VEGFR2, PDGFR, hepatocyte growth factor receptor, and EGFR with IC 50 values of 350, 860, 1100, and 5400 nM, respectively, as well as the nonreceptor tyrosine kinase Syk with an IC 50 value of 460 nM. E6201 does not inhibit ZAP-70 or IKK at 10 μM or PKC activity at 100 μM [1]. E6201 inhibits IL-2 production 48 h after stimulation with the T-cell mitogen PHA-P, with an IC 50 value of 18 nM [1]. E6201 inhibits the proliferation of EGF-stimulated human keratinocytes with an IC 50 value of 160 nM [1]. E6201 suppresses IL-8 production in human keratinocytes 24 h after stimulation with IL-1α or TNFα, with IC 50 values of 60 and 30 nM, respectively [1]. E6201 inhibits TNFα, IL-1, IL-6, and IL-8 production from human PBMCs with IC 50 values of 20, 16, 52, and 53 nM, respectively [1]. E6201 (0.08-20.0 μM) significantly inhibited triple-negative breast cancer (TNBC) cell proliferation and anchorage-independent colony formation in a dose-dependent manner [2]. E6201 (1 μM) inhibits expression of phospho-ERK and induces G1 phase cell cycle arrest, and apoptosis in TNBC [2]. Cell Viability Assay [2] Cell Line: Human TNBC cell lines BT20, HCC70, MDA-MB-231, HCC1806, HCC1937, SUM149 and SUM159 Concentration: 0.00, 0.08, 0.16, 0.31, 0.63, 1.25, 2.50, 5.00, 10.0, 20.0 μM Incubation Time: 5 days Result: Inhibited TNBC cell proliferation and anchorage-independent colony formation in a dose-dependent manner. Western Blot Analysis [3] Cell Line: Human TNBC cell lines BT20, HCC70, MDA-MB-231, HCC1806, HCC1937, SUM149 and SUM159 Concentration: 1 μM Incubation Time: 0, 1, 24 hours Result: pERK expression level showed a rapid (apparent by 1 hour) and sustained (still apparent at 24 hours) decrease in the tested TNBC cell lines following treatment.

E6201 (30 mg/kg; administered via tail vein injection three times per week) inhibits TNBC xenograft tumor growth. E6201 strongly inhibits pERK and Ki-67 expression in xenograft tumor tissues [2]. Animal Model: Female Nod.Scid gamma mice (age 4 to 6 weeks old) bearing MDA-MB-231-LM2 xenograft tumors [2] Dosage: 30 mg/kg Administration: Administered via tail vein injection three times per week for 17 days Result: Compared with mice treated with vehicle control, the E6201-treated mice showed 60% tumor growth suppression.