piperidines and fedratinib

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

HIV can spread by both cell-free and cell-to-cell transmission. Here, we show that many of the amino acid changes in Env that are close to the CD4 binding pocket can affect HIV replication. We generated a number of mutant viruses that were unable to infect T cells as cell-free viruses but were nevertheless able to infect certain T cell lines as cell-associated viruses, which was followed by reversion to the wild type. However, the activation of JAK-STAT signaling pathways caused the inhibition of such cell-to-cell infection as well as the reversion of multiple HIV Env mutants that displayed differences in their abilities to bind to the CD4 receptor. Specifically, two T cell activators, interleukin-2 (IL-2) and phorbol 12-myristate 13-acetate (PMA), both capable of activation of JAK-STAT pathways, were able to inhibit cell-to-cell viral transmission. In contrast, but consistent with the above result, a number of JAK-STAT and mTOR inhibitors actually promoted HIV-1 transmission and reversion. Hence, JAK-STAT signaling pathways may differentially affect the replication of a variety of HIV Env mutants in ways that differ from the role that these pathways play in the replication of wild-type viruses.

Topics: Binding Sites; CD4 Antigens; CD4-Positive T-Lymphocytes; env Gene Products, Human Immunodeficiency Virus; HIV Infections; HIV-1; Humans; Interleukin-2; Janus Kinases; Nitriles; Piperidines; Pyrazoles; Pyrimidines; Pyrroles; Pyrrolidines; Signal Transduction; STAT Transcription Factors; Sulfonamides; Tetradecanoylphorbol Acetate; TOR Serine-Threonine Kinases; Virus Internalization; Virus Replication

Janus kinase (JAK) inhibitors are a promising treatment strategy in several hematological malignancies and autoimmune diseases. A number of inhibitors are in clinical development, and two have already reached the market. Unfortunately, all of them are burdened with different toxicity profiles. To check if the JAK inhibitors of different selectivity evoke different responses on JAK2-dependent and independent cells, we have used three acute myeloid leukemia cell lines with confirmed JAK2 mutation status. We have found that JAK inhibitors exert distinct effect on the expression of BCLXL, CCND1 and c-MYC genes, regulated by JAK pathway, in JAK2 wild type cells in comparison to JAK2 V617F-positive cell lines. Moreover, cell cycle analysis showed that inhibitors alter the cycle by arresting cells in different phases. Our results suggest that observed effect of JAK2 inhibitors on transcription and cell cycle level in different cell lines are associated not with activity within JAK family, but presumably with other off-target activities.

Topics: bcl-X Protein; Cell Cycle; Cell Line, Tumor; Cyclin D1; Down-Regulation; Gene Expression; Humans; Imidazoles; Janus Kinases; Leukemia, Myeloid, Acute; Nitriles; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridazines; Pyrimidines; Pyrroles; Pyrrolidines; Sulfonamides