Volasertib (BI 6727) trihydrochloride is a dihydropteridinone derivative that exhibits potent and selective inhibition of Polo-like kinase 1 (PLK1), PLK2, and PLK3. It acts as an orally active ATP-competitive inhibitor with an IC50 of 0.87 nM against PLK1. Additionally, Volasertib trihydrochloride demonstrates IC50 values of 5 nM and 56 nM against PLK2 and PLK3, respectively. Its mechanism of action includes inducing mitotic arrest and apoptosis. Furthermore, Volasertib trihydrochloride has been shown to possess significant antitumor activity in various cancer models.

Volasertib trihydrochloride (BI 6727 trihydrochloride; 0.01-10000 nM; 72 hours) has EC 50 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, EC 50 =23 nmol/L) and lung (NCI-H460, EC 50 =21 nmol/L), melanoma (BRO, EC 50 =11 nmol/L), and hematopoietic cancers (GRANTA-519, EC 50 =15 nmol/L; HL-60, EC 50 =32 nmol/L; THP-1, E 50 =36 nmol/L and Raji, EC 50 =37 nmol/L) with EC 50 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 (V ss =7.6 L/kg, t 1/2 =46 h) and rats (V ss =22 L/kg, t 1/2 =54 h)[1]. Animal Model: Female BomTac:NMRI-Foxn1 nu 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-Foxn1 nu 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 (V ss =7.6 L/kg, t 1/2 =46 h) and rats (V ss =22 L/kg, t 1/2 =54 h).