(IC50 = 73 nM), and the compound is active in vivo at an oral dose of 7.5 mgkg_ 1 twice daily against a human ovarian cancer xenograft (A2780) grown in nude mice, and is well tolerated. The BMS group has also developed potent and selective aminothiazole CDK1 and CDK2 inhibitors,404,405 culminating in the identification of BMS387032 (85), which has good in vitro potency and in vivo activity. A wide variety of other structures have been identified as CDK2 inhibitors, including SU95 1 6 (86),406 paullones (87),407 pyrazolopyrimidines (88),408 and indenopyrazoles (89).409
Inhibitors of CDK4 are structurally related to those of CDK2, but selectivity is achievable. AstraZeneca has highlighted a series of bis-anilinopyrimidines (90),410 and used structural information derived from CDK2-inhibitor complexes to enhance selectivity for CDK4. Other pharmacophores offering selectivity for CDK4 include the carbazoles (91)411 and (92).412 Of major interest is PD0332991 (93), developed by the Pfizer group;413 this compound inhibits CDK4 and CDK6 (IC50 = 10 and 15 nM, respectively), and has good selectivity against a range of other kinases. Inhibition of cellular growth is seen at 0.1-0.2 mM, and the compound causes growth inhibition in in vivo models of human tumor disease.
7.08.6.3.3 Cyclin-dependent kinase inhibitors in the clinic
Flavopiridol (80) has progressed to multiple Phase II trials,399 and subsets of patients have shown stable disease and partial responses. Toxicities include diarrhea, nausea, vomiting, and some neutropenia. Development in solid tumor disease has stopped, but work in combination with other agents in lymphomas and leukemias continues. Seliciclib (83) has reached Phase II,414 and appears to be well tolerated up to a dose of 2.5 g day_ 1. Disease stabilization has been seen in some patients, and the use of the drug in combination with cytotoxic agents is being studied. The rapid metabolism and modest potency of 83 coupled with high doses may complicate further development. Some patients in the Phase I trials of aminothiazole BMS387032 (85) demonstrated stable disease and regression when 85 was periodically infused at a dose of 5-23 mgm"2. PD0332991 (93), the CDK4 and CDK6 inhibitor, has also entered Phase I studies.
CDK inhibitors appear to have the promise of clinical utility based on early results, but they may have to be used in combination to reach their full potential, and this will need careful scheduling. It is clear that further work will be required to capitalize on the different clinical profiles and therapeutic margins for this group of kinase inhibitors.
7.08.6.4 Aurora Family Kinases
Aurora A and B (and C) are serine/threonine protein kinases that are critical for the proper regulation of mitosis;415,416 they are commonly overexpressed in human tumors,417 and regulate key mitotic events.418 Aurora A is expressed during mitosis, and localizes to the centrosomes and the poles of the mitotic spindle.419 Repression of Aurora A activity in cells delays their entry into mitosis,420 while overexpression of Aurora A can inhibit cytokinesis,421 and compromise the spindle checkpoint. Aurora B is a 'chromosomal passenger protein'422 that plays a key role in kinetochore function, and is required for accurate chromosome alignment and segregation during mitosis.423 Crystal structures of the N-terminal truncated catalytic domain of Aurora A show a relatively large hydrophobic pocket, which is exploited by many of the small-molecule inhibitors to achieve kinase selectivity.424-426
Published work on Aurora kinase inhibitors has focused on compounds 94-96 ( ). VX-680 (94) is a potent inhibitor of Aurora A, B, and C (IC50 = 0.0006, 0.018, and 0.0046 mM, respectively) and shows good selectivity over a broad kinase panel, with some activity against Flt3 (IC50 = 0.03 mM).428 In MCF7 cells, VX-680 (94) inhibits phosphorylation of histone H3 (IC50 = 0.003-0.300 mM), and induces accumulation of cells with 4n DNA content. VX-680 (94) blocks tumor cell proliferation in a panel of tumor cell lines (EC50 = 0.015-0.113 mM) after 96h of treatment. Tumor regression was observed in leukemic (AML: HL-60), pancreatic (MIA PaCa-2), and colon (HCT-116) xenografts following either intraperitoneal or intravenous dosing. As with other Aurora kinase inhibitors, the main dose-limiting toxicity in rodents is mechanism-related neutropenia, which is reversible on drug withdrawal.
Hesperadin (95) is a member of a series of indolinone compounds prepared as cell proliferation inhibitors that inhibit Aurora B kinase (IC50 = 0.25 mM).429 While the compound inhibits a number of other kinases, hesperadin is a potent inhibitor of histone H3 phosphorylation in cells, and has a phenotype similar to VX-680 (94). ZM447439 (96) is a quinazoline that is equiactive against Aurora A and B (IC50 = 0.11 and 0.13 mM, respectively), and which shows good
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