Refametinib

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

一种有效的、非 ATP 竞争性、高选择性的 MEK1/2 变构抑制剂，IC50 分别为 19/47 nM。

A potent, non–ATP-competitive, highly selective, allosteric inhibitor of MEK1/2 with IC50 of 19/47 nM respectively; inhibits anchorage-dependent growth of human cancer cell lines harboring the gain-of-function V600E BRAF mutant with GI50 of 67-89 nM; exhibits complete suppression of ERK phosphorylation at fully efficacious doses in mice and orally bioactive.Liver Cancer Phase 2 Clinical(In Vitro):Refametinib (BAY 869766; RDEA119) selectively binds directly to an allosteric pocket in the MEK1/2 enzymes. Refametinib potently inhibits MEK activity in enzyme inhibition assays in a non-ATP-competitive manner (MEK1 IC50=19 nM, MEK2 IC50=47 nM) determined through incorporation of radioactive phosphate from ATP into ERK as substrate. Refametinib potently inhibits MEK activity as measured by phosphorylation of ERK1/2 across several human cancer cell lines of different tissue origins and BRAF mutational status with EC50 values ranging from 2.5 to 15.8 nM. Refametinib inhibits anchorage-dependent growth of human cancer cell lines harboring the gain-of-function V600E BRAF mutant with GI50 values ranging from 67 to 89 nM. In contrast, Refametinib has significantly less growth-inhibitory potency against cell lines with wild-type BRAF (A431 cells) or MDA-MB-231 cells harboring a BRAF mutation G464V that shows minimal (<2-fold increase) enhancement of inherent kinase activity. Under anchorage-independent conditions, GI50 values for all cell lines tested are similar (40-84 nM). MDA-MB-231 and A431 cells are significantly more sensitive to Refametinib under anchorage-independent conditions. (In Vivo):Refametinib (BAY 869766; RDEA119) is an orally available, potent, non-ATP-competitive, highly selective inhibitor of MEK1/2, which is active in human tumor xenograft models and is well tolerated within the therapeutic exposure range in animals.The human melanoma A375 tumor xenograft is found to be sensitive to Refametinib treatment with 54% and 68% tumor growth inhibition (TGI) seen with 25 and 50 mg/kg/d administered orally on a once daily ×14 schedule. Significant tumor growth delay (TGD) and regressions are also observed in A375 tumors on this once-daily schedule. For example, five to eight complete or partial responses (CR/PR) and up to six tumor-free survivors (TFS) are observed. Administering Refametinib every other day at 100 mg/kg is less effective than daily dosing with either 25 or 50 mg/kg. When Refametinib is dosed on a twice-daily schedule, it is more effective than once-daily schedules.

——

——

BAY 869766 | BAY 86-97661 | RDEA-119 | RDEA119

MAPK/ERK Signaling

MEK

MEK1|MEK2

Cancer

Liver Cancer

923032-37-5

572.3372

C19H20F3IN2O5S

>98% (HPLC)

DMSO: ≥ 31 mg/mL

O=S(C1(C[C@H](O)CO)CC1)(NC2=C(OC)C=C(F)C(F)=C2NC3=CC=C(I)C=C3F)=O

Cyclopropanesulfonamide, N-[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-methoxyphenyl]-1-[(2S)-2,3-dihydroxypropyl]-

(-20℃)

With Ice Pack

≥ 2 years