Mcl-1 inhibitor 6

Mcl-1 inhibitor 6 is an orally active, selective myeloid cell leukemia 1 (Mcl-1) protein inhibitor with a K d of 0.23 nM and a K i of 0.02 μM. Mcl-1 inhibitor 6 possesses superior selectivity over other Bcl-2 family members (Bcl-2, Bcl2A1, Bcl-xL , and Bcl-w , K d >10 μM). Mcl-1 inhibitor 6 is a potent antitumor agent In Vitro Mcl-1 inhibitor 6 has K i s of 10 μM and 1.57μM for Bcl-2 and Bfl-1, respectively. Mcl-1 inhibitor 6 (1, 5 μM; for 48 h) significantly induces apoptosis in a concentration-dependent manner. Mcl-1 inhibitor 6 (0.1, 5 μM; for 4 h) remarkably upregulates PARP cleavage in H929 cells in a concentration-dependent manner. Mcl-1 inhibitor 6 (for 72 h) shows antiproliferative activities against the tumor cell lines (H929, MV4-11, SK-BR-3, NCI-H23; IC 50 =0.36-3.02 μM). Mcl-1 inhibitor 6 shows ideal selectivity against CML cell line K562 (IC 50 >30 μM). MCE has not independently confirmed the accuracy of these methods. They are for reference only. Apoptosis AnalysisCell Line: H929 cells Concentration: 1, 5 μM Incubation Time: For 48 hours Result: Significantly induced apoptosis in a concentration-dependent manner. Western Blot AnalysisCell Line: H929 cells Concentration: 0.1, 0.5, 1, 5 μM Incubation Time: For 4 hours Result: Remarkably upregulated PARP cleavage in H929 cells in a concentration-dependent manner. In Vivo Mcl-1 inhibitor 6 (compound 40; 60 mg/kg with PO or 20 mg/kg with IP; every two days for 14 days) shows desired in vivo tumor growth inhibition activity . Mcl-1 inhibitor 6 (3 mg/kg with IV or 10 mg/kg with PO) has a T 1/2 of 2.3 hours, a CL of 15.18 mL/min•kg by IV . MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: Balb/c nude female mice (7 weeks) loaded with MV4-11 xenografts Dosage: 60 mg/kg (PO) or 20 mg/kg (IP) Administration: IP or PO; every two days for 14 days Result: Showed desired in vivo tumor growth inhibition activity (T/C = 37.30% and 5.52% by po and ip administration, respectively). Animal Model: SD rats (200-250 g) Dosage: 3 mg/kg (IV) or 10 mg/kg (PO) (Pharmacokinetic Analysis) Administration: IV or PO Result: Had a T 1/2 of 2.3 hours, a CL of 15.18 mL/min•kg by IV. Had a T 1/2 of 2.1 hours, a CL of 36.8 mL/min•kg and a C max of 2012.95 ng/mL. Form:Solid IC50& Target:Mcl-1 0.23 nM (Kd) Mcl-1 0.02 μM (Ki) Bcl-2 >10 μM (Kd) Bcl-2 10 μM (Ki) Bcl2A1 >10 μM (Kd) Bcl-xL >10 μM (Kd) Bcl-W >10 μM (Kd) Bfl-1 1.57 μM (Ki)

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