Pd0325901

phosphorylation of ERK1, a downstream substrate of MEK. The compound is also active in vivo, where at twice daily oral doses of 48-200 mgkg _ 1 to mice bearing human tumor xenografts, it shows significant inhibition of tumor growth and is well tolerated.386

Compound 78 has progressed to the clinic,387 where it was given at a dose of 1600 mg once daily or 800 mg twice daily, with the latter regime resulting in better exposure. Side effects seen included fatigue, skin rash, and diarrhea, but target therapeutic plasma levels were achieved, and stable disease was seen in ~ 30% of patients. However, Phase II trials in patients with advanced NSCLC, breast, colon, and pancreatic cancers, dosing at 800 mg twice daily, no objective responses were seen.377 This may be due to the relatively poor pharmacokinetic and physicochemical properties of the compound, leading to variable absorption and blood levels. A second-generation inhibitor, PD0325901 (79), which has a number of advantages including improved aqueous solubility, achieved by introducing a hydrophilic side chain, is already in Phase I studies.388

7.08.6.2.3 Structural studies

The unique mode of action of the allosteric inhibitors of MEK has stimulated a great deal of work to understand how they interact with the enzyme, and, recently, structures of a bromo derivative of inhibitor 79, bound to both the MEK1 and MEK2 isoforms, have been solved.389 Both enzymes have what appear to be unique binding pockets close to the ATP-binding site to which molecules such as 79 bind. When these molecules bind, they induce the same type of conformational changes that activating phosphorylations produce, closing the active site, but resulting in a catalytically inactive kinase through disruption of the competent orientation of catalytic residues.

7.08.6.2.4 Future directions

Just as the high selectivity of imatinib (1) is attributable to its distinct mechanism of inhibition, the high selectivity of inhibitors such as 78 and 79 appears to be linked to their unique mechanism of action. If these compounds prove active at tolerated doses, this approach could provide impetus for looking at similar inhibition mechanisms for other clinically relevant kinases. The reduced potential for nontarget-based pharmacology may also make such an approach of interest in other disease areas.

7.08.6.3 Cyclin-Dependent Kinases

7.08.6.3.1 Cyclin-dependent kinases and cancer

The CDK family of serine/threonine kinases is an essential component of the cell cycle machinery of every mammalian cell, and is critical to effective cell proliferation.390,391 CDK activity is tightly controlled throughout the cell cycle by a group of activating proteins termed cyclins,392 which are transiently expressed throughout the replication process, and activate the required CDK. While the CDKs are rarely overexpressed in tumors, there is clear evidence that the activating cyclins can be amplified393 and that natural inhibitors of the CDKs, such as p27, can be downregulated.393 The consequent growth advantage obtained by cells under these circumstances is a common feature in human cancers, and has generated great interest in CDKs as potential selective targets for the treatment of the disease.394,395 While apoptosis is commonly the result of cell cycle inhibition of tumor cells, normal cycling cells simply arrest. CDK1, CDK2, and CDK4 are directly involved in cell cycle progression; CDK5, CDK7, and CDK9 are less directly involved, but may still be worthwhile targets.

7.08.6.3.2 Cyclin-dependent kinase inhibitors

CDK inhibitors typically fall into two broad classes; those which inhibit CDK1, CDK2, and CDK5, and those inhibiting CDK4 and CDK6.390 That said, UCN-01 (101)396 and flavopiridol (80) (Figure 16),397 both derived from natural product leads and among the first agents to be identified, inhibit the majority of CDKs, in addition to several other kinases. More recently, the availability of structural information from CDK2-inhibitor complexes398,399 (and the detailed interactions of small molecules within the ATP-binding site) have resulted in the development of relatively selective inhibitors.

The purine derivatives olomucine (81)400 and purvalanol A (82)401 and seliciclib ((R)-roscovitine, CYC202, 83)402 are all more selective inhibitors of CDK2. Seliciclib inhibits a range of CDKs, including CDK1, CDK2, CDK7, and CDK9 at micromolar levels, and this translates into cell cycle blocks at both the G1/S and G2/M checkpoints, consistent with the inhibition profile of the enzymes.

The Pharmacia group has identified a range of 3-aminopyrazole derivatives, including PNU-292137 (84), as CDK2 inhibitors403 (IC50 = 37 nM) that also inhibit CDK1 and CDK5. Inhibition of HCT116 cell growth is observed

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