nu-6027 and Neoplasms

Cyclin-dependent kinase 2 (CDK2) drives the progression of cells into the S- and M-phases of the cell cycle. CDK2 activity is largely dispensable for normal development, but it is critically associated with tumor growth in multiple cancer types. Although the role of CDK2 in tumorigenesis has been controversial, emerging evidence proposes that selective CDK2 inhibition may provide a therapeutic benefit against certain tumors, and it continues to appeal as a strategy to exploit in anticancer drug development. Several small-molecule CDK2 inhibitors have progressed to the clinical trials. However, a CDK2-selective inhibitor is yet to be discovered. Here, we discuss the latest understandings of the role of CDK2 in normal and cancer cells, review the core pharmacophores used to target CDK2, and outline strategies for the rational design of CDK2 inhibitors. We attempt to provide an outlook on how CDK2-selective inhibitors may open new avenues for cancer therapy.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Cyclin-Dependent Kinase 2; Drug Design; Humans; Neoplasms; Protein Binding; Protein Conformation; Protein Kinase Inhibitors

Modulation of DNA repair pathways in oncology has been an area of intense interest in the last decade, not least as a consequence of the promising clinical activity of poly(ADP-ribose) polymerase (PARP) inhibitors. In this review article, we highlight inhibitors of the phosphatidylinositol 3-kinase related kinase (PIKK) family as of potential interest in the treatment of cancer, both in combination with DNA-damaging therapies and as stand-alone agents.

Topics: Animals; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins; DNA; DNA Repair; DNA-Activated Protein Kinase; DNA-Binding Proteins; Humans; Models, Molecular; Neoplasms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Tumor Suppressor Proteins

A Phenotypic Drug Discovery strategy was applied to study a set of pyrimidine analogs prepared by means of intramolecular oxidation-reduction reactions of N-substituted-N-(2,6-disubstituted-5-nitro-4-pyrimidinyl)aminoacetic acid methyl esters in basic media. The combined and rational use of specific assays allowed in short time reducing from all possible cellular targets to those involved in metaphase to anaphase transition.

Topics: Anaphase; Antineoplastic Agents; Cell Cycle; Cell Line, Tumor; Drug Discovery; Humans; Metaphase; Neoplasms; Oxidation-Reduction; Pyrimidines; Structure-Activity Relationship