n-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide and Multiple-Myeloma

Janus kinases (JAKs) are involved in various signalling pathways exploited by malignant cells. In multiple myeloma (MM), the interleukin-6/JAK/signal transducers and activators of transcription (IL-6/JAK/STAT) pathway has been the focus of research for a number of years and IL-6 has an established role in MM drug resistance. JAKs therefore make a rational drug target for anti-MM therapy. CYT387 is a novel, orally bioavailable JAK1/2 inhibitor, which has recently been described. This preclinical evaluation of CYT387 for treatment of MM demonstrated that CYT387 was able to prevent IL-6-induced phosphorylation of STAT3 and greatly decrease IL-6- and insulin-like growth factor-1-induced phosphorylation of AKT and extracellular signal-regulated kinase in human myeloma cell lines (HMCL). CYT387 inhibited MM proliferation in a time- and dose-dependent manner in 6/8 HMCL, and this was not abrogated by the addition of exogenous IL-6 (3/3 HMCL). Cell cycling was inhibited with a G(2)/M accumulation of cells, and apoptosis was induced by CYT387 in all HMCL tested (3/3). CYT387 synergised in killing HMCL when used in combination with the conventional anti-MM therapies melphalan and bortezomib. Importantly, apoptosis was also induced in primary patient MM cells (n=6) with CYT387 as a single agent, and again synergy was seen when combined with conventional therapies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzamides; Blotting, Western; Bone Marrow; Boronic Acids; Bortezomib; Cell Cycle; Cell Proliferation; Cells, Cultured; Extracellular Signal-Regulated MAP Kinases; Humans; Interleukin-6; Janus Kinase 1; Melphalan; Multiple Myeloma; Phosphorylation; Pyrazines; Pyrimidines; Signal Transduction; STAT3 Transcription Factor; Stromal Cells