An orally bioavailable, ATP-competitive, pyrazolo-quinazoline, MPS1 inhibitor (IC50=182nM, Ki=0.99nM) that is shown to act in a reversible and time-dependent manner. It demonstrates selectivity for MPS1 against a panel of 60 kinases, displaying activity against only three kinases, CK2, MELK, and NEK6 (<10uM), but not against other mitotic kinases including PLK1, CDK1, Aurora A, Aurora B, or the SAC kinase BUB1, in an in vitro kinase assay. It promotes massive SAC (spindle assembly checkpoint) override (EC50=65nM) in nocodazole-arrested U20S cells and elicits a reduction in the G1 and G2/M phase of the cell cycle in A2780 ovarian cancer cells, similar to RNAi-mediated MPS1 silencing. In addition, it is shown to inactivate SAC, delocalize kinetochore components, and inhibit the proliferation of select cancer cell lines (IC50 ~1uM), without marked activity among a panel of 127 normal cell lines. Also, it inhibits A2780 tumor xenograft growth in mice (90mg/kg/day, o.s., in vivo) by 53% without marked body weight loss. Formula: C35H39F3N8O3 Molecular Weight: 676.3 Solubility: DMSO (10mg/ml, clear, colorless solution) Storage and Stability: Lyophilized powder may be stored at -20C. Stable for 12 months at -20C. Reconstitute with sterile ddH2O. Aliquot to avoid repeated freezing and thawing. Store at -20C. For maximum recovery of product, centrifuge the original vial after thawing and prior to removing the cap. Further dilutions can be made in assay buffer.
Molecular Weight:
676.3
Purity:
~98% (HPLC)
Form:
Supplied as a white powder.
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