Volasertib trihydrochloride

Volasertib (BI 6727) trihydrochloride is an orally active, highly potent and ATP-competitive Polo-like kinase 1 (PLK1) inhibitor with an IC50 of 0.87 nM. Volasertib trihydrochloride inhibits PLK2 and PLK3 with IC50s of 5 and 56 nM, respectively. Volasertib trihydrochloride induces mitotic arrest and apoptosis. Volasertib trihydrochloride, a dihydropteridinone derivative, shows marked antitumor activity in multiple cancer models[1][2].

Signaling Pathways >> Apoptosis >> Apoptosis

Research Areas >> Cancer

Signaling Pathways >> Cell Cycle/DNA Damage >> Polo-like Kinase (PLK)

Volasertib trihydrochloride (BI 6727 trihydrochloride; 0.01-10000 nM; 72 hours) has EC50 values of 11 to 37 nmol/L in multiple cell lines[1]. Volasertib trihydrochloride (10-1000 nM; 24 hours) results accumulation of cells with 4N DNA content, indicative of a cell cycle block in G2-M phase[1]. Volasertib trihydrochloride (100 nM; 24-72 hours) induces cell apoptosis at 48 hours[1]. Cell Proliferation Assay[1] Cell Line: Multiple cell lines Concentration: 0.01-10000 nM Incubation Time: 72 hours Result: Inhibited proliferation of multiple cell lines derived from various cancer tissues, including carcinomas of the colon (HCT 116, EC50=23 nmol/L) and lung (NCI-H460, EC50=21 nmol/L), melanoma (BRO, EC50=11 nmol/L), and hematopoietic cancers (GRANTA-519, EC50=15 nmol/L; HL-60, EC50=32 nmol/L; THP-1, E50=36 nmol/L and Raji, EC50=37 nmol/L) with EC50 values of 11 to 37 nmol/L. Apoptosis Analysis[1] Cell Line: NCI-H460 cells Concentration: 100 nM Incubation Time: 24, 48, 72 hours Result: G2-M arrest at 24 hours was followed by induction of apoptosis at 48 hours. Cell Cycle Analysis[1] Cell Line: NCI-H460 cells Concentration: 10, 30, 100, 300, 1000 nM Incubation Time: 24 hours Result: Resulted in accumulation of cells with 4N DNA content, indicative of a cell cycle block in G2-M phase.

Volasertib trihydrochloride (BI 6727 trihydrochloride; A total weekly dose of 50 mg/kg; Oral; once a week, twice a week, or daily; for 40 days) shows comparable efficacy in human colon carcinoma xenograft models[1]. Volasertib trihydrochloride (15, 20, or 25 mg/kg/day; i.v.; 2 consecutive days per week; for 40 days) leads to significant tumor growth delay and even tumor regression in human colon carcinoma xenograft models [1]. Volasertib trihydrochloride (70 mg/kg given once weekly or 10 mg/kg daily; oral) significantly delays tumor growth in a non-small cell lung carcinoma xenograft model derived from NCI-H460 cells[1]. Volasertib (a single dose of 40 mg/kg; iv) causes a significant (13-fold) increase in mitotic cells in HCT 116 tumor-bearing nude mice[1]. Volasertib has high volume of distribution and a long terminal half-life in mice (Vss=7.6 L/kg, t1/2=46 h) and rats (Vss=22 L/kg, t1/2=54 h)[1]. Animal Model: Female BomTac:NMRI-Foxn1nu mice (Taconic) were grafted s.c. with HCT 116 human colon carcinoma cells (ATCC CCL-247)[1] Dosage: A total weekly dose of 50 mg/kg Administration: Oral; once a week, twice a week, or daily; for 40 days Result: Showed comparable efficacy and were well tolerated. Animal Model: Female BomTac:NMRI-Foxn1nu mice and male Wistar rats of the strain Crl:WI[1] Dosage: 35 mg/kg (mice) or 10 mg/kg (rat) (Pharmacokinetic Analysis) Administration: IV 5-minute infusion; a single dose 5-minute infusion Result: Had high volume of distribution and a long terminal half-life in mice (Vss=7.6 L/kg, t1/2=46 h) and rats (Vss=22 L/kg, t1/2=54 h).