CFI-400945 fumarate

CFI-400945 fumarate is a potent, selective and orally bioavailable PLK4 inhibitor with a Ki and an IC50 of 0.26 nM and 2.8 nM, respectively.

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

Research Areas >> Cancer

PLK4:2.8 nM (IC50)

AURKA:140 nM (IC50)

AURKB/INCENP:98 nM (IC50)

TIE2/TEK:22 nM (IC50)

TRKA:6 nM (IC50)

TRKB:9 nM (IC50)

CFI-400945 (compound 48) shows potent inhibitory activities against a panel of kinases, including PLK4, TRKA, TRKB, AURKA, AURKB/INCENP, and TIE2/TEK, with IC50s of 2.8, 6, 9, 140, 98, 22 nM, and EC50s of 12, 84, 88, 510, 102, 117 nM, respectively. CFI-400945 exhibits growth inhibition effects on breast, lung, ovarian and colon cancer cells. The IC50s (in μM) are as follows: SKBr-3 (5.3), Cal-51 (0.26), BT-20 (0.058), A549 (0.005), OVCAR-3 (0.018), SW620 (0.38), Colo-205 (0.017), and HCT116+/+ (0.004) [1]. CFI-400945 inhibits autophosphorylation of PLK4 at serine 305 with an EC50 value of 12.3 nM in cells overexpressing PLK4. Cancer cells treated with CFI-400945 exhibit effects consistent with PLK4 kinase inhibition, including dysregulated centriole duplication, mitotic defects, and cell death[2].

Oral administration of CFI-400945 (3.0, 9.4 mg/kg) to mice bearing human cancer xenografts results in the significant inhibition of tumor growth at doses that are well tolerated. Increased antitumor activity is observed in PTEN-deficient compared to PTEN wild-type cancer xenografts. The maximum tolerated dose for once-daily administration of CFI-400945 is estimated to be 7.5-9.5 mg/kg[2].

Active PLK4 is purified and used to measure PLK4 activity, using an indirect ELISA detection system. PLK1, PLK2, PLK3, AURKA, and AUKB/INCENP compound inhibition are determined using FRET-based homogeneous assay kits from Invitrogen. The assays are performed with ATP concentrations of 25, 60, and 80 μM, respectively, for PLK1, PLK2, and PLK3 and ATP concentrations of 20 and 128 μM, respectively, for AURKA and AURKB/INCENP[1].

MDA-MB-468, MCF-7, HCC1954, MDA-MB-231, SKBr-3, Cal-51, and BT-20 breast cancer cells are treated with 10 nM to 50 μM CFI-400945 for 5 days. Cell viability is measured using SRB assay[2].

Mice: To treat an established tumor, CFI-400945 and the vehicle (water) are administered by oral gavage (2.5-20 mg/kg), and 5-FU and carboplatin are administered by intraperitoneal injection to mice as described in the text. Animal weights are monitored daily, and tumor volume is measured three times per week[2].

[1]. Sampson PB, et al. The discovery of Polo-like kinase 4 inhibitors: identification of (1R,2S).2-(3-((E).4-(((cis).2,6-dimethylmorpholino)methyl)styryl). 1H.indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one (CFI-400945) as a potent, orally active antitumor agent. J Med Chem. 2015 Jan 8;58(1):147-69.

[2]. Mason JM, et al. Functional characterization of CFI-400945, a Polo-like kinase 4 inhibitor, as a potential anticancer agent. Cancer Cell. 2014 Aug 11;26(2):163-76.

Volasertib (BI 6727) | BI 2536 | Centrinone | Rigosertib sodium | CFI-400945 | GSK461364 | GW843682X | TAK-960 | NMS-1286937 | Poloxin | LFM-A13 | Ro3280 | MLN0905 | SBE 13 hydrochloride | HMN-214