alvocidib and palbociclib

The role of cyclin-dependent kinases (CDKs) in regulating the transition of cell cycle steps makes this class of enzymes a suitable target for cancer therapy. Three different generations of CDKs inhibitors have been developed so far. Third-generation compounds (i.e. selective CDK4/6 inhibitors) are the most promising ones, due to their limited toxicity and high in vivo activity. To date, three compounds have entered the therapy, namely Palbociclib, Ribociclib and Abemaciclib. Herein we review the medicinal chemistry aspects of these drugs, with some references to very similar analogues that have been published.

Topics: Aminopyridines; Benzimidazoles; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Dose-Response Relationship, Drug; Humans; Molecular Structure; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; Structure-Activity Relationship

Imbalance of the cyclin D and cyclin-dependent kinase (CDK) pathway in cancer cells may result in diversion away from a pathway to senescence and toward a more proliferative phenotype. Cancer cells may increase cyclin D-dependent activity through a variety of mechanisms. Therapeutic inhibition of CDKs in tumors to negate their evasion of growth suppressors has been identified as a key anticancer strategy. In this review, we outline the development of CDK inhibitory therapy in breast cancer, including the initial experience with the pan-CDK inhibitor flavopiridol and the next generation of oral highly selective CDK4 and CDK6 inhibitors PD0332991 (palbociclib), LEE011 (ribociclib), and LY2835219 (abemaciclib). Data from phase I and II studies in estrogen receptor-positive (ER+) breast cancer demonstrate promising efficacy with manageable toxic effects, chiefly neutropenia. We discuss these studies and the phase III studies that are accruing or nearing completion. We describe the application of such therapy to other breast cancer settings, including HER2-positive breast cancer and the adjuvant treatment of early breast cancer. We also discuss potential concerns surrounding the combination of CDK inhibitors with chemotherapy and their effects on repair of double-strand DNA breaks in cancer cells. Oral highly selective CDK inhibitors show great promise in improving the outcomes of patients with ER+ breast cancer, although caution must apply to their combination with other agents and in the early breast cancer setting.

Topics: Aminopyridines; Breast Neoplasms; Cell Cycle; Clinical Trials as Topic; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; DNA Breaks, Double-Stranded; Estrogen Receptor alpha; Female; Flavonoids; Humans; Piperazines; Piperidines; Protein Kinase Inhibitors; Purines; Pyridines

The t(8;21) is one of the most frequent chromosomal translocations associated with acute myeloid leukemia (AML). We found that t(8;21) AML were extremely sensitive to THZ1, which triggered apoptosis after only 4 h. We used precision nuclear run-on transcription sequencing (PROseq) to define the global effects of THZ1 and other CDK inhibitors on RNA polymerase II dynamics. Inhibition of CDK7 using THZ1 caused wide-spread loss of promoter-proximal paused RNA polymerase. This loss of 5' pausing was associated with accumulation of polymerases in the body of a large number of genes. However, there were modest effects on genes regulated by 'super-enhancers'. At the 3' ends of genes, treatment with THZ1 suppressed RNA polymerase 'read through' at the end of the last exon, which resembled a phenotype associated with a mutant RNA polymerase with slower elongation rates. Consistent with this hypothesis, polyA site-sequencing (PolyA-seq) did not detect differences in poly A sites after THZ1 treatment. PROseq analysis after short treatments with THZ1 suggested that these 3' effects were due to altered CDK7 activity at the 5' end of long genes, and were likely to be due to slower rates of elongation.

Topics: 3' Flanking Region; 5' Flanking Region; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Proliferation; Cyclic N-Oxides; Cyclin-Dependent Kinase 9; Cyclin-Dependent Kinase-Activating Kinase; Cyclin-Dependent Kinases; Flavonoids; Gene Expression Regulation, Leukemic; Humans; Indolizines; Myeloid Cells; Phenylenediamines; Piperazines; Piperidines; Piperidones; Protein Kinase Inhibitors; Pyridines; Pyridinium Compounds; Pyrimidines; Pyrroles; RNA Polymerase II; Translocation, Genetic