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MNK1/2-IN-7 (compound 20j) is an orally available inhibitor of MNK1/2 with anticancer activity and hERG safety. MNK1/2-IN-7 also inhibits the phosphorylation of eIF4E, inhibiting the MNK/eIF4E signaling pathway and cancer cell proliferation. MNK1/2-IN-7 is synergistic with Ibrutinib (HY-109970)[1]. | [in vivo]
MNK1/2-IN-7 (5 mg/kg; po; single dose) exhibits acceptable exposure and bioavailability in rats and is orally effective [1].
MNK1/2-IN-7 (10 mg/kg; po; 17 d) effectively caused tumor regression in a DOHH2 xenograft mouse model without affecting mouse body weight. MNK1/2-IN-7 also has a synergistic effect with Ibrutinib (HY-109970)[1].
Pharmacokinetic Analysis in SD Rats[1]
| Route | Dose (mg/kg) | T1/2 (h) | Tmax (h) | Cmax (μg/mL) | AUC0-t (h·μg/mL) | AUC0-∞ (h·μg/mL) | Cl (mL/h/kg) | F (%) | | i.v. | 1 | 13.8 | 0.083 | 1.3 | 10.0 | 14.4 | 70.2 | / | | p.o. | 5 | >24 | 6 | 1.5 | 23.3 | NA | / | 46.86 |
| Animal Model: | GCB-DLBCL DOHH2 xenograft tumors model in mouse[1] | | Dosage: | 10 mg/kg | | Administration: | po; once daily for 17 days; or combination of 3 mg/kg Ibrutinib | | Result: | Resulted tumor regression
Achieved a greater TGI value of 54% for combination group at the end of treatment compared to the value for a single administration or ibrutinib administration.
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| [IC 50]
MNK1: 4.4 nM (IC50, [1]); MNK2: 0.4 nM (IC50, [1]) | [References]
[1] Yuan X, et al. Development of an Imidazopyridazine-Based MNK1/2 Inhibitor for the Treatment of Lymphoma[J]. Journal of Medicinal Chemistry, 2024. |
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