Abstract
Uncontrolled cell proliferation is the hall mark of many cancers, and is typically manifested by a deregulation of the cell-division cycle. CDKs play critical roles in regulating cell cycle, apop- tosis and cell differentiation. AG-024322 is a multitargeted CDK inhibitor that has been shown to induce cancer cell apoptosis and de- monstrate significant antitumor activity in hu-man tumor xenograft models. This compound is under clinical development as an intravenous anticancer agent. AG-024322 exhibited moder-ate to high systemic clearance across preclini-cal species. In vitro metabolism in human liver microsomes and hepatocytes demonstrates that glucuronidation and oxidation represent the major metabolic pathways of AG-024322. The experiments of chemical inhibition and micro-somes containing individual CYP or UGT iso-forms revealed that CYP3A and UGT1A1 appear to predominantly mediate AG-024322 oxidation and glucuronidation, respectively. Formation kinetics of the two pathways in human liver mi-crosomes suggested that the glucuronidation activity of AG-024322 was approximately 3-fold higher as compared to CYP-mediated oxidation, contributing approximately 37% and 13% of the total clearance, respectively, based on the pro-jected human clearance. UGT1A1 is a poly-morphic isoform involved in glucuronidation of bilirubin. It is of concern if glucuronidation via UGT1A1 plays a major role in the elimination of AG-024322 in humans as competitive inhibition of UGT1A1 has been associated with toxicity (Gilbert and Crigler-Najjar syndromes). There-fore, this information was used to influence the clinical study design to only include subjects having constitutive expression of UGT1A1 in the first human study, thereby decreasing the potential risk of toxicity to patients.
Highlights
AG-024322, N-({5-[3-(4,6-difluoro-1H-benzimidazol-2yl)-1H-indazol-5-yl]-4-methylpyridin-3-yl}methyl)ethanamine, is a multitargeted CDK inhibitor under development as an anticancer agent
Metabolic stability of [14C]AG-024322 in liver microsomes and hepatocytes are presented in Table 1 as percent of parent drug remaining after incubation in the preparations for rat, dog, monkey and human
The corresponding disappearance half-life was generated from the available time course data. [14C]AG-024322 depleted most extensively in rat liver microsome with 11% of radiochromatogram of the parent drug remaining at 1-hour incubation time, followed by dog (55%)
Summary
AG-024322, N-({5-[3-(4,6-difluoro-1H-benzimidazol-2yl)-1H-indazol-5-yl]-4-methylpyridin-3-yl}methyl)ethanamine, is a multitargeted CDK inhibitor under development as an anticancer agent. AG-024322 is a potent ATP-competitive inhibitor of the cell cycle kinases CDK1, CDK2, and CDK4, with kinetic inhibition constants (Ki) in the 1-3 nM range [1]. CDKs play a key role in regulating the cell cycle progression and to a large degree control cellular transitions from growth phases into phases associated with DNA replication and mitosis by phosphorylating several cellular proteins [2,3,4]. AG-024322 inhibits phosphorylation of CDK substrates in cells, resulting in cell arrest and broad-spectrum anti-proliferative activity, and has been shown to induce cancer cell apoptosis and significant antitumor efficacy in human tumor xenograft models with tumor growth inhibition (TGI) ranging from 32% to 86.4% [5]. The volume of distribution greatly exceeded the volume of total body water across species (9 to 15 l/kg), and was consistent with rapidly and Openly accessible at http://www.scirp.org/journal/HEALTH/
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