Victoria Feher

POLO-LIKE KINASE INHIBITORS

Polo-like kinases (PLKs) are a family of serine/threonine kinases that play crucial roles in multiple stages of mitosis. PLK1 is the most studied member of the family. It is overexpressed in a wide spectrum of cancer types and is a promising target in oncology. Most of PLK1 inhibitors are ATP-competitive. Despite the structural similarities among various kinases, several inhibitors are selective. Some areas of the PLK1 active site are important for selectivity against other kinases. These include a small pocket formed by Leu 132 in the hinge region, a bulky phenylalanine and a small cysteine at the bottom and in the roof of the ATP pocket, respectively, and an unusual concentration of positively charged residues in the solvent-exposed region. Many ATP-competitive inhibitors are heterocyclic systems able to interact with the unique features of the PLK1 binding site. Other inhibitors target regions outside the ATP pocket, such as the substrate binding domain or a hydrophobic pocket, formed when the kinase is in the inactive conformation. An alternative approach to obtain specificity and to overcome drug resistance often associated with kinase inhibitors is the inhibition of the polo-box domain (PBD) of PLK1. The PBD is unique for the family of PLKs and is essential for PLK functions; so it is a useful target for the development of selective and potent inhibitors for clinical uses. In this review some PLK inhibitors are reported, focusing on chemical structures, structure-activity-relationships (SAR) and biological activities. The great potential of these compounds could open promising perspectives. Moreover, a combination of polo-like kinases inhibitors with other anticancer drugs might offer new opportunities for cancer therapy.

Structure-based design and synthesis of pyrrole derivatives as MEK inhibitors.

A novel series of pyrrole inhibitors of MEK kinase has been developed using structure-based drug design. Optimization of the series led to the identification of potent inhibitors with good pharmaceutical properties.

Discovery of TAK-960: An orally available small molecule inhibitor of polo-like kinase 1 (PLK1).

Using structure-based drug design, we identified and optimized a novel series of pyrimidodiazepinone PLK1 inhibitors resulting in the selection of the development candidate TAK-960. TAK-960 is currently undergoing Phase I evaluation in adult patients with advanced solid malignancies.

Structure-based design and SAR development of 5,6-dihydroimidazolo[1,5-f]pteridine derivatives as novel Polo-like kinase-1 inhibitors.

Using structure-based drug design, we identified a novel series of 5,6-dihydroimidazolo[1,5-f]pteridine PLK1 inhibitors. Rational improvements to compounds of this class resulted in single-digit nanomolar enzyme and cellular activity against PLK1, and oral bioavailability. Compound 1 exhibits >7 fold induction of phosphorylated Histone H3 and is efficacious in an in vivo HT-29 tumor xenograft model.

Abstract B270: Profiling the biochemical and cellular activities of TAK‐901, a potent multi‐targeted Aurora‐B kinase inhibitor

Aurora A, B, and C comprise a family of serine‐threonine protein kinases that are key cell cycle regulators ensuring an orderly and accurate execution of mitosis and cell division. Aurora A localizes to centrosomes and spindle poles and is required for mitotic spindle assembly and centrosome maturation, whereas Aurora B is a chromosome passenger protein essential for phosphorylation of histone H3, chromosome segregation, and cytokinesis. Aurora A and B are overexpressed in many malignancies, making them attractive therapeutic targets. Derived from the azacarboline scaffold representing a unique kinase hinge‐binder chemotype, TAK‐901 is a novel inhibitor of Aurora A, B, and C kinases with IC50 values in the low nanomolar range. It potently inhibits Aurora A‐TPX2 and Aurora B‐INCENP (IC50 = 21 and 15 nM, respectively) and is a time‐dependent, tight binding inhibitor of Aurora B‐INCENP. Dissociation of TAK‐901 from Aurora B‐INCENP was slow with a t1/2 of 920 minutes, and the affinity constant for TAK‐901 binding to Aurora B‐INCENP was determined to be 0.02 nM. TAK‐901 induced inhibition of cell proliferation in cultured human cancer cell lines from different tissues with IC50s ranging from 40 to 500 nM. Consistent with Aurora B inhibition, TAK‐901 treatment produced polyploidy in human PC3 prostate cancer and HL60 acute myeloid leukemia cells as measured by immunofluorescence and flow cytometry. Examination of a broad panel of kinases revealed that multiple kinases, including FLT3, FGFR and the Src family kinases, were inhibited by TAK‐901 with IC50 values similar to those for Aurora A and B. In cells, TAK‐901 suppressed the Flt3 and FGFR2 autophosphorylation with IC50 values close to that of Aurora B as measured by cellular histone H3 phosphorylation, whereas the IC50s for inhibition of cellular Src and BcrAbl were 20‐fold weaker. In a panel of pathway specific reporter‐based cell models, TAK‐901 inhibited the NFkB and JAK/STAT pathways with submicromolar potency. However, phosphorylation or subcellular localization of the signaling mediators NFkB and STAT5 were unaffected by TAK‐901 treatment. The expression of a subset of NFkB‐regulated genes was altered by TAK‐901. Furthermore, TAK‐901 treated human PBMCs exhibited multiple differentially expressed genes, as identified using gene expression profiling by microarray analysis, which were subsequently confirmed by quantitative RT‐PCR. The mechanism by which TAK‐901 alters expression of these genes remains unknown and is under investigation. Altogether, these findings have led to increased understanding of the biological activities of TAK‐901 and identification of potential novel biomarkers for clinical use. TAK‐901 is currently in Phase I clinical trials. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B270.