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Figure 13 Second-generation VEGFR kinase inhibitors.

Further refinement of ZD6474 has resulted in ZD2171 (59) (Figure 13), which is significantly more potent than the earlier compound, and has lost the activity against EGFR.337 Two structurally related analogs of these quinazolines are Kirin's KRN633 (60) and Pfizer's thienylpyridine (61).338'339 Pfizer has also described CP547,632 (62), which has entered Phase I trials, as has AG013736 (63).340'341 CEP-7055 (64) is an N,N-dimethylglycine ester prodrug of CEP-5214 that Cephalon is partnering with Sanofi-Synthelabo.342 GlaxoSmithKline has described preclinical studies with GW654652 (65), and a group from Merck has recently published work with N-(1,3-thiazol-2-yl)pyridine-2-amine 66.

7.08.5.9 Fibroblast Growth Factor Receptor (FGFR) 7.08.5.9.1 Fibroblast growth factor receptor and cancer

To date, 23 different fibroblast growth factors have been identified, including FGF-1 (acidic FGF) and FGF-2 (basic FGF or bFGF).347-349 Four RTKs (FGFR1-4) have been identified for these growth factors, and are characterized by having an extracellular domain that contains three different immunoglobulin domains, with the first two separated by an acidic region.350 Due to the existence of a large number of splice variants in the ligand-binding domain, it is possible for the four FGFR genes to encode a much larger number of receptor proteins.351 There is a clear link between various FGF family members (including FGF-2) and prostate cancer, where the growth factors are implicated in both proliferation and angiogenesis/invasion.352,353 The involvement of FGF family members and their receptors is also emerging in bladder (FGFR3),354 renal cell (FGF-2 and FGF-5),355 and testicular (FGF-4)356 cancers.

7.08.5.9.2 Fibroblast growth factor receptor inhibitors357

Curiously, only a few FGFR inhibitors have been described, and achieving good selectivity over VEGF inhibition looks to be a significant challenge. SU5402 (67) (Figure 14) from the ubiquitous indolinone series has good potency toward FGFR1 (IC50 = 20 nM) but is equiactive against KDR and has relatively poor physical properties.358 PD173074 (4) is also from a well-known chemical class of inhibitors, but achieves good selectivity over PDGFR-b, Src, EGFR, and IGF-1R, with an IC50 of 26 nM against FGFR1.156'359 Finally, 1-oxo-3-phenyl-1H-indene-2-carboxamide (68) is a relatively weak FGFR1 inhibitor (IC50 = 4.7 mM), but may represent a novel starting point for future work.360

7.08.6 Serine/Threonine Kinases

7.08.6.1 Serine/Threonine Kinases and Cancer

There are considerably more serine/threonine kinases than tyrosine kinases in the human kinome, but despite this numerical advantage, no serine/threonine kinase inhibitor is currently approved for use in cancer. Promising data in the MEK and cell cycle (Aurora/CDK) areas has been reported, and these kinases will be discussed in detail alongside the less well-studied proteins Raf, Akt, PDK1, and PKC. Other kinases with potential value as oncology targets include ROCK (rho kinase),361 Plk (polo-like kinase),362 P70S6 kinase,363 TGF-b receptor-associated kinases (ALK1-ALK7),364 CK1e,365 PAK4,366 and Nek family kinases.367

Some progress in finding inhibitors for these kinases has been made, with some encouraging results against ROCK. Thus, H-7 (69) was identified as an ATP-competitive inhibitor,368 and modification resulted in HA-1077 (Fasudil, 70),369 which has modest activity for the kinase; recent work in the isoquinoline series has provided more potent inhibitors.370 Another ROCK inhibitor is Y-27632 (71),371 which has an IC50 of 0.25 mM; the structure of this inhibitor bound to PKA372 should aid the design of more potent inhibitors.

7.08.6.2 Mitogen-Activated Protein Kinase/Extracellular Signal-Related Kinase Kinase (MEK) (MEK1 and MEK2)

7.08.6.2.1 Mitogen-activated protein kinase/extracellular signal-related kinase kinase and cancer

MEK (MAP kinase kinase) is a key signal amplification point in the Ras-MEK-ERK (extracellular signal-related kinase) transduction pathway driving growth and survival signaling in mammalian cells.373 Two closely related isoforms, MEK1 and MEK2, are ubiquitously expressed, and are unusual in being dual specificity kinases, phosphorylating both serine/ threonine and tyrosine residues. MEK phosphorylation of its substrates, ERK1 and ERK2, results in a large amplification of growth factor signals derived from RTKs and other sources. MEK (MEK1 and MEK2) has not been identified as an oncogene product374 but constitutive activation does result in cellular transformation and this is implicated in the progression of a broad range of human tumors.375'376 Recent clinical trials with MEK inhibitors have demonstrated activity in human tumors and confirm these enzymes as important targets for treatment of human tumor disease.377

7.08.6.2.2 Inhibitors of mitogen-activated protein kinase/extracellular signal-related kinase kinase

The first inhibitor of MEK identified was the flavone PD98059 (72) (Figure 15).378The molecule was identified from library screening, and, although not potent (IC50 = 2-7 mM), it prevents activation of MEK.379 The compound does not compete directly with ATP, and this led to the hypothesis that the compound inhibited the enzyme by binding to an unphosphorylated site on MEK, preventing activation. Physicochemical limitations and activity against other enzymes prevented further development of 72.

A variety of natural products have been identified as MEK inhibitors, including (10E)-hymenialdisine (73),380 lactone Ro-09-2210 (74),381 and the closely related lactone L-783277 (75),382 the last being the most potent (IC50 = 4nM). DuPont identified U-0126 (76) as a potent MEK inhibitor (IC50 = 72nM);383 this agent is not competitive with ATP, and is more potent against unactivated MEK. Analogs of 76 have been synthesized, and the (Z,Z) isomers usually possess most potency,384 although the area is complex, since such molecules often cyclize when dissolved in dimethyl sulfoxide.

More conventional inhibitors of MEK are represented by 3-cyanoquinoline (77).385 This compound is ATP-competitive and highly potent (IC50 = 2 nM) and with antiproliferative activity against LoVo cells at 5 nM, although it is unclear if this activity is solely the result of MEK inhibition. The most advanced MEK inhibitors are those represented by Parke-Davis's CI-1040 (PD1843 5 2 , 78).373,386 This agent is not competitive with ATP, and acts as an allosteric inhibitor of the enzyme, which prevents activation of the kinase by blocking phosphorylation. Because of this mechanism, the compound is highly selective (MEK1 IC50 = 17 nM) against the enzyme, which translates into antiproliferative activity in cells at concentrations of ~0.1 mM. The activity in cells correlates well with inhibition of

Figure 15 MEK inhibitors.

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