SCH-772984

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

一种新型有效的选择性 ERK1/ERK2 抑制剂，IC50 分别为 4 nM/1 nM。

A novel potent and selective inhibitor of ERK1/ERK2 with IC50 of 4 nM/1 nM, respectively; is highly selective, with only seven kinases of 300 showing >50% inhibition at 1 uM; prevents MEK-mediated ERK phosphorylation, reduces pCRAF S289/S296/S301 phosphorylation; has nanomolar cellular potency in tumor cells with mutations in BRAF, NRAS, or KRAS and induces tumor regressions in xenograft models.Colon Cancer Phase 1 Clinical(In Vitro):SCH772984 (300 nM; 24-48hours) results in a G1 arrest in SCH772984-sensitive melanoma cells.SCH772984 (3-300 nM; 24 hours) inhibits ERK and RSK phosphorylation.SCH772984 shows EC50 values less than 500 nM in approximately 88% and 49% of BRAF-mutant (n=25) or RAS-mutant (n=35) tumor lines, respectively.(In Vivo):SCH772984 (12.5-50 mg/kg; i.p.; twice daily for 14 days) leads to 98% tumor regression.Dose-dependent antitumor activity is also observed in the KRAS-mutant pancreatic MiaPaCa model, with 36% regression at 50 mg/kg twice daily. Importantly, tumor regression is accompanied by robust inhibition of ERK phosphorylation in tumor tissue. SCH772984 is well tolerated on this schedule as measured by morbidity, lethality, or body weight loss.

SCH772984 (300 nM; 24-48hours) results in a G1 arrest in SCH772984-sensitive melanoma cells.SCH772984 (3-300 nM; 24 hours) inhibits ERK and RSK phosphorylation.SCH772984 shows EC50 values less than 500 nM in approximately 88% and 49% of BRAF-mutant (n=25) or RAS-mutant (n=35) tumor lines, respectively.Cell Cycle Analysis Cell Line:LOX cells (SCH772984-sensitive melanoma cells) Concentration:300 nMIncubation Time:24, 48 hours Result:Revealed a G1 arrest as well as an increase in the sub-G1 fraction indicative of apoptosis. Western Blot Analysis Cell Line:LOX BRAFV600E melanoma cells Concentration:3, 10, 30, 100, 300 nM Incubation Time:24 hours Result:A dose-dependent inhibition of phosphorylation of the ERK substrate RSK (T359/S363 phospho-RSK), and also inhibited phosphorylation of residues in the activation loop of ERK itself (T202/Y204 and T185/Y187 of ERK1 and ERK2, respectively).

SCH772984 (12.5-50 mg/kg; i.p.; twice daily for 14 days) leads to 98% tumor regression.Dose-dependent antitumor activity is also observed in the KRAS-mutant pancreatic MiaPaCa model, with 36% regression at 50 mg/kg twice daily. Importantly, tumor regression is accompanied by robust inhibition of ERK phosphorylation in tumor tissue. SCH772984 is well tolerated on this schedule as measured by morbidity, lethality, or body weight loss. Animal Model:Female nude mice bearing human LOX BRAFV600E tumors Dosage:12.5, 25, 50 mg/kg Administration:Intraperitoneal injection; twice daily for 14 days Result:Tumor regressions were observed at all doses, such as 17% at 12.5 mg/kg, 84% at 25 mg/kg, and 98% at 50 mg/kg).

SCH 772984 | SCH772984

MAPK/ERK Signaling

ERK

ERK1|ERK2|MEK1

Cancer

Colon Cancer

942183-80-4

587.6742

C33H33N9O2

>98% (HPLC)

DMSO: ≥ 51 mg/mL

O=C([C@H]1CN(CC(N2CCN(C3=CC=C(C4=NC=CC=N4)C=C3)CC2)=O)CC1)NC5=CC6=C(NN=C6C7=CC=NC=C7)C=C5

3-Pyrrolidinecarboxamide, 1-[2-oxo-2-[4-[4-(2-pyrimidinyl)phenyl]-1-piperazinyl]ethyl]-N-[3-(4-pyridinyl)-1H-indazol-5-yl]-, (3R)-

(-20℃)

With Ice Pack

≥ 2 years