Zm447439

Figure 17 Aurora kinase inhibitors.

selectivity over a range of other kinases.423 Published studies with compound 96 shows that it causes a dose-dependent increase in 4n DNA, due to a failure of cytokinesis, that is consistent with the proposed mechanism of action. Furthermore, compound 96 selectively induced apoptosis in cycling cells but had relatively little effect on Grarrested MCF-7 cells when profiled in in vitro clonigenicity assays.423

7.08.6.5 Raf Kinase 7.08.6.5.1 Raf and cancer

The three closely related Raf kinases, A-raf, B-raf and C-raf, are serine/threonine kinases that are activated by ras-GTP and/or PKC-a. Raf, in turn, activates MEKby phosphorylation of S218 and S222, transducing the signal from upstream Ras down the Ras-Raf-MEK-ERK pathway.430 Since about 30% of human tumors possess activating ras mutations, the downstream effector Raf is an attractive target for anticancer therapy. It is now recognized that activating somatic mutations to B-raf are common in some human tumors such as melanoma.431

7.08.6.5.2 Inhibitors of Raf

A variety of small-molecule approaches to the inhibition of Raf have been reported,430'432 the most advanced being BAY 43-9006 (97) (Figure 18).433,434 The compound was developed from a bis-aryl lead series, and interacts at the ATP-binding site of the kinase (B-raf IC50 = 22 nM). Compound 97 has additional kinase activity, notably against c-Kit, Flt3, and KDR, and also inhibits the common V599E mutant of B-raf. It shows oral activity in mice bearing a range of human tumor xenografts with mutant K-ras, and entered Phase I clinical studies in 2000.435 These studies showed it to be well tolerated, and, at a dose of 400 mg twice daily, side effects were diarrhea, skin rash, and fatigue. Some disease stabilization was seen and BAY 43-9006 (97) (Nexavar, Sorafenib) has recently been approved for the treatment of renal cell carcinoma.436 Further work in this series has been undertaken to address the poor aqueous solubility of 97.437

7.08.6.6 Akt/3-Phosphoinositide-Dependent Kinase 1 (PDK1) 7.08.6.6.1 Akt/3-phosphoinositide-dependent kinase 1 and cancer

Akt (PKB) is a serine/threonine kinase within the AGC kinase group having a high homology with both PKA and PKC. Three closely related isoforms (Akt1, Akt2, and Akt3) are known, and constitute part of the PI3' kinase signaling pathway, frequently inappropriately activated in human cancers.438 A compelling piece of evidence, linking increased Akt signaling with cancer, is that loss of PTEN activity, a tumor suppressor encoding an Akt-deactivating phosphatase, is observed in 30-50% of human tumors.439,440

PDK1 (3-phosphoinositide-dependent kinase 1), another serine/threonine kinase member of the AGC group, is also part of the PI3' kinase signaling pathway, but is upstream of Akt. Phosphoinositides produced by PI3' kinase recruit the

plectrin homology domains of Akt, causing conformational changes in the Akt activation loop, which can then be phosphorylated and activated by PDK1. There is compelling evidence for the role of all three enzymes (PI3' kinase, PDK1,441 and Akt) in aberrant signaling in cancer, which makes all these enzymes attractive oncology targets.

7.08.6.6.2 Inhibitors of Akt/3-phosphoinositide-dependent kinase 1

While Akt/PDK1 are attractive targets for cancer chemotherapy, progress in finding potent and selective inhibitors has been relatively slow. A series of substituted quinoxalines (98)442 have been identified that have some selectivity for the individual isoforms of Akt and that may bind at an allosteric site. Analogs of 98 suggest a requirement to inhibit Akt1 and Akt2 to achieve maximal pro-apoptotic response in vitro. Recent work has identified a series of azepanes (99) that were designed using crystal structures of probe compounds, bound to the related kinase PKA,443 and the structure of the natural product kinase inhibitor (-)-balanol. A recent crystal structure of Akt444 supports conclusions drawn from this work.

Selective inhibitors of PDK1 have been described by a Berlex group, and include compounds such as BX-320 (100).445 This compound inhibits PDK1 (IC50 = 40 nM) and inhibits cell growth at 0.1—0.4 mM, appearing to promote apoptosis in tumor cells but not in normal cells. The compound is also active in vivo when given orally at 200 mgkg_ 1 twice daily in a mouse model of metastatic melanoma, and binds to the ATP-binding site of the kinase according to an x-ray crystal structure.445

7.08.6.7 Protein Kinase C 7.08.6.7.1 Protein kinase C and cancer

The three major isoform classes of PKC, known as conventional (PKC-a, PKC-b, and PKC-g), novel (PKC-S, PKC-e, PKC-Z, and PKC-9), and atypical (PKC-Z and PKC-i), constitute a family of serine/threonine kinase involved in multiple signal transduction pathways.446 The enzymes are involved in signal transduction from classical RTKs and G-protein-coupled receptors, and play a role in nuclear hormone signaling with much of the specificity of the activated isoforms appearing to derive from their subcellular localization. The various isoforms require other co-factors for activation (e.g., 1,2-sn-diacylglycerol, calcium, phosphatidyl-L-serine, or phorbol esters), in addition to phosphorylation of serine or threonine residues and membrane translocation to be fully active.446 There is a limited understanding of the role of PKC in tumor initiation and growth,447 and the complexity of PKC function and activity has made the rational choice of isoform targets difficult.

7.08.6.7.2 Inhibitors of protein kinase C

A number of natural products have been identified as inhibitors of the PKC family,448 and most synthetic work has used these agents as starting points. A series of staurosporine derivatives, such as UCN-01 (101), midostaurin (CGP4 1 251, 102),450 Ro 31-8220 (103),451 and LY 33 3 531 (104)452 (Figure 19), have been described as PKC inhibitors, and have progressed to clinical evaluation. UCN-01 (101) inhibits PKC-a (IC50 = 7nM), but also has activity against a wide range of other kinases such as the CDKs.453 It was administered by intravenous infusion to patients in a Phase I trial in cancer,398 and shown to have a very long half-life (400-1500 h), which may be related to its

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