cp-724714 and Neoplasms

Cyclin-dependent kinases 8 (CDK8) regulates transcriptional process via associating with the mediator complex or phosphorylating transcription factors (TF). Overexpression of CDK8 has been observed in various cancers. It mediates aberrant activation of Wnt/β-catenin signaling pathway, which is initially recognized and best studied in colorectal cancer (CRC). CDK8 acts as an oncogene and represents a potential target for developing novel CDK8 inhibitors in cancer therapeutics. However, other study has revealed its contrary role. The function of CDK8 is context dependent. Even so, a variety of potent and selective CDK8 inhibitors have been discovered after crystal structures were resolved in two states (active or inactive). In this review, we summarize co-crystal structures, biological mechanisms, dysregulation in cancers and recent progress in the field of CDK8 inhibitors, trying to offer an outlook of CDK8 inhibitors in cancer therapy in future.

Topics: Colorectal Neoplasms; Cyclin-Dependent Kinase 8; Drug Discovery; Humans; Mediator Complex; Molecular Structure; Neoplasms; Oncogenes; Protein Kinase Inhibitors; Wnt Signaling Pathway

The 4-aminoquinazoline core is an interesting pharmacophore and its applications in medicinal chemistry are wide spread. The core has been used for making many kinase inhibitors in past few years. Many researcher demonstrated 4-aminoquinazoline derivatives as specific kinase inhibitors, including tyrosine kinase and serine/theronine kinases. A number of anticancer drugs with 4-aminoquinazoline core are in the market, e.g. gefitinib, erlotinib, afatinib, lapatinib, decomitinib etc. 4-aminoquinazoline derivatives are applied for target specific treatment of lung, breast, colon, prostate cancers. In this review, we discussed the current development of 4-aminoquinazoline derivatives as kinase inhibitors and their uses as anticancer agents in recent years.

Topics: Animals; Antineoplastic Agents; Chemistry Techniques, Synthetic; Humans; Neoplasms; Protein Kinase Inhibitors; Quinazolines

CP-724,714 is an orally available, small molecule, potent HER-2 tyrosine kinase inhibitor under development for the treatment of advanced HER2-overexpressing cancers. In this study, the influence of baseline clinical characteristics and pathophysiological variables on the pharmacokinetics (PK) of CP-724,714, and the correlation between PK exposure and safety were examined in patients treated in the First-in-Human trial. PK and safety were also simulated for a Phase 2 trial at the recommended Phase 2 dose (RP2D) to assess if the simulated PK exposures of CP-724,714 covered the preclinically predicted efficacious concentrations, and if the predicted incidence of hepatic toxicities (>or=CTC grade 3) was acceptable.. Patients (n = 30) with advanced malignant HER2 positive solid tumors were enrolled in this open label dose-escalation study, and treated with daily oral dosing of CP-724,714 in 21-day cycles at the following dose levels: 250 mg QD, 250 mg BID, 400 mg BID, and 250 mg TID. PK parameter values were estimated using noncompartmental techniques. PK exposure parameters were correlated with the baseline pathophysiological variables, clinical characteristics, and safety. The simulations of PK exposures and the incidence of >or=grade 3 liver toxicity at the recommended Phase 2 dose were performed by nonparametric bootstrap (n = 1,000).. C (max) and AUC increased in an approximate dose proportional manner. The terminal t (1/2) was approximately 4.5 h, and was constant across the dose range from 250 to 400 mg. There was some accumulation with BID and TID dosing with a mean AUC accumulation ratio approximately 1.2-1.5, consistent with the t (1/2). Inter-patient variability in PK parameters was 31-65%, resulting in a considerable overlap of systemic exposure parameters (C (max) and AUC) at higher doses (i.e., 250 mg TID and 400 mg BID), as expected for the narrow dose range. Significant correlations were observed for body size and oral clearance (CL/F) (r = 0.574, P = 0.001) and oral steady-state volume of distribution (V (dss)/F) (r = 0.669, P = 0.0001). The most frequently encountered toxicities were elevated ALT and AST, hyperbilirubinemia, rash, asthenia, and nausea/vomiting (N/V). The steady-state AUC0-24 h was significantly correlated with the elevation of total bilirubin (r = 0.670, P = 0.001), ALT (r = 0.548, P = 0.002), and AST (r = 0.461, P = 0.010). The simulation of the Phase 2 trial at 250 mg BID predicted that the 95% confidence interval of the simulated mean concentrations of CP-724,714 were above the preclinically predicted efficacious concentrations throughout the majority of the dosing interval. The probability for >or=33% incidence of grade 3 or greater elevations of liver function test (LFT) was low (1.1%).. CP-724,714 demonstrates linear single-dose and multiple-dose PK. Both CL/F and V (dss)/F correlate with body size. Elevations of ALT, AST, and total bilirubin positively correlate with the steady-state AUC0-24 h. The Phase 2 trial simulation suggests that CP-724,714 will be well tolerated and that PK exposures will exceed the preclinically predicted efficacious level at the recommended Phase 2 dose (250 mg BID), supporting further evaluation of CP-724,714 in the Phase 2 trial.

Topics: Adult; Aged; Algorithms; Antineoplastic Agents; Area Under Curve; Breast Neoplasms; Chemical and Drug Induced Liver Injury; Chromatography, Liquid; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Half-Life; Humans; Liver Function Tests; Middle Aged; Neoplasm Metastasis; Neoplasms; Protein-Tyrosine Kinases; Quinazolines; Receptor, ErbB-2; Tandem Mass Spectrometry

To develop a population pharmacokinetic (popPK) model for CP-724,714, a novel HER2 tyrosine kinase inhibitor is under development for the treatment of advanced HER2 positive cancers.. Concentration-time data (n = 484) from 30 cancer patients receiving daily oral CP-724,714 at doses of 250 mg QD, 250 mg BID, 250 mg TID, and 400 mg BID in 21-day cycles in an open label First-in-Human dose-escalation study were evaluated. Serum concentrations of CP-724,714 were obtained after single dose and at steady state. Nonlinear mixed effect analysis in NONMEM using first order conditional estimation with interaction (FOCEI) was performed. The effect of covariates was assessed. Diagnostic plots, decrease of objective function value (>7.8), bootstrapping, and predictive check were used as model selection criteria.. A 2-compartment first-order absorption pharmacokinetic (PK) model with inter-subject variability (ISV) on the apparent oral elimination clearance (CL/F), apparent central volume of distribution (V1/F), apparent peripheral volume of distribution (V2/F), and first-order oral absorption rate constant (ka), interoccasion variability (IOV) on CL/F, and body weight (WT) as covariate on CL/F was developed. There was no evidence of dose-dependent and/or time-dependent PK. CL/F increased with increasing WT. The ISV of CL/F was reduced by approximately 20% with WT as a covariate. Age, race, and liver metastasis did not influence CP-724,714 disposition.. A popPK model was developed that adequately described the pharmacokinetics of CP-724,714. WT was identified as a covariate on CL/F that reduced ISV and improved model performance. Future studies will further assess the importance of WT as a pharmacokinetic covariate. The proposed popPK model can be used to simulate CP-724,714 Phase 2/3 trials.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Body Weight; Data Interpretation, Statistical; Dose-Response Relationship, Drug; Female; Humans; Liver Neoplasms; Middle Aged; Models, Biological; Multicenter Studies as Topic; Neoplasms; Nonlinear Dynamics; Quinazolines; Receptor, ErbB-2; Tissue Distribution

To test the tolerability, safety, and recommended phase II dose of CP-724,714, a reversible, highly selective, oral HER2 tyrosine kinase inhibitor in patients with advanced solid tumor malignancies that express HER2.. A phase I trial evaluated escalating doses of CP-724,714, administered daily in 21-day cycles. Pharmacokinetics/pharmacodynamics were evaluated in serial blood samples and in pretreatment and posttreatment tumor and skin biopsies.. Thirty female patients [median age, 51 years (range, 37-71); median performance status, 1 (range, 0-1)] received CP-724,714 at four dose levels: 250 mg once daily (4 patients), 250 mg twice daily (15 patients), 250 mg thrice daily (6 patients), and 400 mg twice daily (5 patients). Dosing at 400 mg twice daily and 250 mg thrice daily was not feasible due to reversible, cholestatic liver dysfunction. Treatment-related adverse events were nausea (58%), asthenia (23%), hyperbilirubinemia (27%), elevated transaminases (30%), and skin rash (30%); neither diarrhea nor cardiomyopathy was observed. No objective responses were observed in 28 evaluable patients; 8 (29%) patients had stable disease. Twenty-seven (96%) patients received prior trastuzumab and were heavily pretreated (median prior chemotherapy, 6; range, 1-11). Systemic exposure exceeded the in vivo efficacy threshold required in preclinical studies.. Dose-limiting toxicities included hyperbilirubinemia, elevated alanine aminotransferase, thrombocytopenia and pulmonary embolus. Although the protocol-specified maximum tolerated dose of CP-724,714 was 250 mg thrice daily, the recommended phase II dose was 250 mg twice daily due to excessive late-cycle hepatotoxicity. Despite extensive prior treatment, 29% of patients had stable disease. A phase II trial has been initiated in patients with breast cancer.

Topics: Adult; Aged; Antineoplastic Agents; Female; Humans; Middle Aged; Neoplasms; Protein Kinase Inhibitors; Quinazolines; Receptor, ErbB-2