ABSTRACT
Deregulation of the cyclin-dependent kinases (CDKs) has been implicated in the pathogenesis of multiple cancer types. Consequently, CDKs have garnered intense interest as therapeutic targets for the treatment of cancer. We describe herein the molecular and cellular effects of CCT068127, a novel inhibitor of CDK2 and CDK9. Optimized from the purine template of seliciclib, CCT068127 exhibits greater potency and selectivity against purified CDK2 and CDK9 and superior antiproliferative activity against human colon cancer and melanoma cell lines. X-ray crystallography studies reveal that hydrogen bonding with the DFG motif of CDK2 is the likely mechanism of greater enzymatic potency. Commensurate with inhibition of CDK activity, CCT068127 treatment results in decreased retinoblastoma protein (RB) phosphorylation, reduced phosphorylation of RNA polymerase II, and induction of cell cycle arrest and apoptosis. The transcriptional signature of CCT068127 shows greatest similarity to other small-molecule CDK and also HDAC inhibitors. CCT068127 caused a dramatic loss in expression of DUSP6 phosphatase, alongside elevated ERK phosphorylation and activation of MAPK pathway target genes. MCL1 protein levels are rapidly decreased by CCT068127 treatment and this associates with synergistic antiproliferative activity after combined treatment with CCT068127 and ABT263, a BCL2 family inhibitor. These findings support the rational combination of this series of CDK2/9 inhibitors and BCL2 family inhibitors for the treatment of human cancer.
Subject(s)
Antineoplastic Agents/pharmacology , Cyclin-Dependent Kinase 2/metabolism , Cyclin-Dependent Kinase 9/metabolism , Melanoma/metabolism , Purines/pharmacology , Aniline Compounds/pharmacology , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclin-Dependent Kinase 2/genetics , Cyclin-Dependent Kinase 9/genetics , HCT116 Cells , HT29 Cells , Humans , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Purines/chemistry , Retinoblastoma Protein/metabolism , Sulfonamides/pharmacologyABSTRACT
PURPOSE: This study intended to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RD) of trabectedin combined with carboplatin in patients with advanced solid tumors. PATIENTS AND METHODS: Carboplatin-pretreated patients received carboplatin AUC 4 (Group 1), whereas carboplatin-naïve patients received carboplatin AUC 5 (Group 2) as a 1-h i.v. infusion followed by trabectedin at dose range from 0.5-1.2 mg/m(2) in the schedule of 3-h/every-3-weeks. Pharmacokinetic (PK) sampling was performed in the first 2 cycles. RESULTS: Forty-four patients were treated and evaluable for safety and dose-limiting toxicities (DLTs). In Group 1, at trabectedin 1.0 mg/m(2), cumulative hematological toxicity was found in all patients and 1/10 patients had DLTs. The RD was considered trabectedin 0.8 mg/m(2) combined with carboplatin AUC 4. Although no DLT occurred at this dose level, frequent dose delays (28.6%) and the 4-week cycle re-scheduling (66.7%) were required. In Group 2, DLTs occurred at trabectedin 0.8 mg/m(2) (3/8 patients), 1.0 mg/m(2) (3/10 patients) and 1.2 mg/m(2) (2/2 patients) with cumulative hematological toxicity associated with an important number of transfusions. In this group, neither the MTD nor the RD were established. Promising antitumor activity was found for this carboplatin/trabectedin combination; especially in patients with advanced ovarian cancer and soft tissue sarcoma. No significant PK drug-drug interaction occurred. CONCLUSIONS: This study established a trabectedin dose of 0.8 mg/m(2) combined with carboplatin AUC 4 and given every 4 weeks as the most feasible schedule in carboplatin-pretreated patients. Dose and cycle recommendations for carboplatin-naïve patients warrant further evaluation.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Neoplasms/drug therapy , Adolescent , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Area Under Curve , Carboplatin/pharmacokinetics , Dioxoles/pharmacokinetics , England , Female , Humans , Infusions, Intravenous , Male , Maximum Tolerated Dose , Middle Aged , Neoplasms/pathology , Spain , Tetrahydroisoquinolines/pharmacokinetics , Trabectedin , Treatment Outcome , Young AdultABSTRACT
The cyclin-dependent kinase (CDK) inhibitor seliciclib (1, CYC202) is in phase II clinical development for the treatment of cancer. Here we describe the synthesis of novel purines with greater solubility, lower metabolic clearance, and enhanced potency versus CDKs. These compounds exhibit novel selectivity profiles versus CDK isoforms. Compound αSßR-21 inhibits CDK2/cyclin E with IC(50)=30 nM, CDK7-cyclin H with IC(50)=1.3 µM, and CDK9-cyclinT with IC(50)=0.11 µM; it (CCT68127) inhibits growth of HCT116 colon cancer cells in vitro with GI(50)=0.7 µM; and shows antitumour activity when dosed p.o. at 50mg/kg to mice bearing HCT116 solid human tumour xenografts.
Subject(s)
Adenosine/analogs & derivatives , Cyclin-Dependent Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Purines/chemistry , Adenosine/chemical synthesis , Adenosine/chemistry , Adenosine/pharmacokinetics , Adenosine/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Female , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Purines/chemical synthesis , Purines/pharmacokinetics , Purines/pharmacology , Roscovitine , Xenograft Model Antitumor AssaysSubject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Carcinoma, Renal Cell/diagnostic imaging , Carcinoma, Renal Cell/etiology , Carcinoma, Renal Cell/therapy , Humans , Kidney Neoplasms/diagnostic imaging , Kidney Neoplasms/etiology , Kidney Neoplasms/therapy , Radiography , Risk Factors , von Hippel-Lindau Disease/complicationsABSTRACT
The treatment of lung cancer is important as it represents a global health burden. Many therapies are used including surgery, radiotherapy, chemotherapy, laser therapy, stenting, supportive care and biological agents. Treatment for individual patients is best assessed by a multidisciplinary approach. This article focuses on treatment with chemotherapy and radiotherapy.