Novel-targeted therapy for hematological malignancies with JAK and HDAC dual inhibitors

Therapy of JAK inhibitors or HDAC inhibitors alone for hematological malignancies Janus kinases (JAKs) are a family of intracellular nonreceptor tyrosine kinases comprising JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2), which play a critical role in transducing cytokine-mediated signals via the JAK-signal transducer and activator of transcription (STAT) pathway - and are also implicated in the pathogenesis of various hematological malignancies and autoimmune diseases (1). Recently, TYK2 has been demonstrated to be highly expressed in all cases of human anaplastic large cell lymphomas (5). [...]JAK inhibitors have been developed to treat various hematological malignancies. The JAK1/2 inhibitor ruxolitinib was successfully approved by US FDA in 2011 for patients with MF or polycythemia vera. [...]clinical trials of ruxolitinib for multiple myeloma, acute myeloid leukemia and other hematopoietic neoplasms are currently ongoing. In our case, the JAK and HDAC dual inhibitors showed remarkable in vitro potency against several hematological cancer cell lines, validating the rationality of biology-oriented target combination; however, the poor pharmacokinetic (PK) properties of our compounds severely compromised their in vivo efficacy. [...]the favorable PK property, which will facilitate the translation of in vitro activity to in vivo efficacy, is another important aspect of multitarget compound design.