piperidines and Myeloproliferative-Disorders

An enhanced understanding of the importance of Janus kinase (JAK) and signal transducer and activator of transcription (STAT) signalling in multiple disease states has led to an increasing applicability of therapeutic intervention with JAK inhibitors. These agents have revolutionised treatments for a heterogeneous group of disorders, such as myeloproliferative neoplasms, rheumatoid arthritis, inflammatory bowel disease, and multiple immune-driven dermatological diseases, exemplifying rapid bench-to-bedside translation. In this Therapeutics paper, we summarise the currently available data concerning the successes and safety of an array of JAK inhibitors and hypothesise on how these fields could develop.

Topics: Arthritis, Rheumatoid; Humans; Inflammatory Bowel Diseases; Janus Kinase Inhibitors; Myeloproliferative Disorders; Nitriles; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Pyrrolidines; Signal Transduction; Sulfonamides

Farnesyltransferase inhibitors (FTIs) are small-molecule inhibitors that selectivly inhibit farnesylation of a number of intracellular substrate proteins such as Ras. Preclinical work has revealed their ability to effectively inhibit tumor growth in vitro and in vivo in animal models across a wide range of malignant phenotypes. Acute myeloid leukemias (AMLs) are appropriate disease targets in that they express relevant biologic targets such as Ras, MEK, AKT, and others that may depend upon farnesyl protein transferase activity to promote cell proliferation and survival. Indeed, different intracellular proteins are substrates for prenylation. Interruption of prenylation may prevent substrates from undergoing maturation which may result in the inhibition of cellular events that depend on the function of those substrates. Phase I trials in AML and myelodysplasia have demonstrated biologic and clinical activities as determined by target enzyme inhibition, low toxicity, and both complete and partial responses. As a result, phase II trials have been initiated in order to further validate clinical activity and to identify downstream signal transduction targets that may be modified by these agents. It is anticipated that these studies will serve to define the optimal roles of FTIs in patients with these hematologic malignancies and provide insight into effective methods by which to combine FTIs with other agents.

Topics: Alkyl and Aryl Transferases; Benzodiazepines; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Resistance, Neoplasm; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Imidazoles; Leukemia, Myeloid, Acute; Mitogen-Activated Protein Kinase 1; Myeloproliferative Disorders; Piperidines; Protein Prenylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Pyridines; Quinolones; ras Proteins; rho GTP-Binding Proteins