PHA-680626

• CAT Number: I008735
• CAS Number: 398493-74-8
• Molecular Formula: C23H26N6O2S
• Molecular Weight: 450.561
• Purity: ≥95%
• Synonyms: PHA680626; PHA 680626; PHA-680626.;4-(4-methylpiperazin-1-yl)-N-(5-(2-(thiophen-2-yl)acetyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzamide.
• Target: PLK1 inhibitor
• Solubility: Soluble in DMSO, not in water
• Storage: 0 - 4 °C for short term, or -20 °C for long term
• IUPAC Name: 4-(4-methylpiperazin-1-yl)-N-[5-(2-thiophen-2-ylacetyl)-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazol-3-yl]benzamide
• InChI: InChI=1S/C23H26N6O2S/c1-27-8-10-28(11-9-27)17-6-4-16(5-7-17)23(31)24-22-19-14-29(15-20(19)25-26-22)21(30)13-18-3-2-12-32-18/h2-7,12H,8-11,13-15H2,1H3,(H2,24,25,26,31)
• InChIKey: BMCKWRUTJXVUFF-UHFFFAOYSA-N
• SMILES: CN1CCN(CC1)C2=CC=C(C=C2)C(=O)NC3=NNC4=C3CN(C4)C(=O)CC5=CC=CS5

PHA-680626 is a potent and selective PLK inhibitor. PHA-680626 exhibits anti-proliferative and pro-apoptotic activity on Imatinib-resistant chronic myeloid leukemia cell lines and primary CD34+ cells by inhibition of both Bcr-Abl tyrosine kinase and Aurora kinases. PHA-680626 inhibits Plk1 (IC50 = 0.53 μM), Plk2 (IC50 = 0.07 μM) and Plk3 (IC50 = 1.61 μM).

Reference

1:Leuk Res. 2008 Dec;32(12):1857-65. doi: 10.1016/j.leukres.2008.04.012. Epub 2008 Jun 2. PHA-680626 exhibits anti-proliferative and pro-apoptotic activity on Imatinib-resistant chronic myeloid leukemia cell lines and primary CD34+ cells by inhibition of both Bcr-Abl tyrosine kinase and Aurora kinases.Gontarewicz A,Balabanov S,Keller G,Panse J,Schafhausen P,Bokemeyer C,Fiedler W,Moll J,Brümmendorf TH, PMID: 18514829 DOI: 10.1016/j.leukres.2008.04.012 Abstract: Emergence of resistance to Imatinib complicates the treatment of chronic myeloid leukemia (CML). Second-generation Bcr-Abl inhibitors are capable to overcome resistance mediated by most mutations except T315I. As this mutation is causative for approximately 20% of clinically observed resistances, the need for novel treatment strategies becomes obvious. Here, we report on a novel kinase inhibitor PHA-680626 exhibiting strong inhibitory activity on both Bcr-Abl and Aurora kinases. Significant anti-proliferative and pro-apoptotic effects were observed in human BCR-ABL positive cell lines and murine BaF3 cells ectopically expressing wt BCR-ABL or the Imatinib-resistant BCR-ABL mutants M351T, E255K and, T315I. Treatment with PHA-680626 decreased phosphorylation of CrkL and histone H3. As CrkL represents a typical downstream target of Bcr-Abl while histone H3 phosphorylation is an indicator for Aurora kinase B activity, these findings indicate that effects of PHA-680626 are mediated via inhibition of both pathways. Moreover, high anti-proliferative activity of PHA-680626 was observed in primary CD34+ cells derived from CML patients at diagnosis or in blast crisis as well as from an individual harbouring the T315I mutation. Thus, both Bcr-Abl and Aurora kinase inhibition contribute to the efficacy of PHA-680626 against Imatinib-resistant BCR-ABL positive leukemias, particularly those harbouring the T315I mutation.