sgi-1776 and Neoplasms

With the rise of immuno-oncology, small-molecule modulators targeting immune system and inflammatory processes are becoming a research hotspot. This work mainly focuses on key kinases acting as central nodes in immune signaling pathways. Although over thirty small-molecule kinase inhibitors have been approved by FDA for the treatment of various cancers, only a few are associated with immuno-oncology. With the going deep of the research work, more and more immunity protein kinase inhibitors are approved for clinical trials to treat solid tumors and hematologic malignancies by FDA, which remain good prospects. Meanwhile, in-depth understanding of biological function of immunity protein kinases in immune system is pushing the field forward. This article focuses on the development of safe and effective small-molecule immunity protein kinase inhibitors and further work needs to keep the promises of these inhibitors for patients' welfare.

Topics: Humans; Immune System; Immunotherapy; Inflammation; Neoplasms; Protein Kinase Inhibitors

The three Pim kinases are a small family of serine/threonine kinases regulating several signaling pathways that are fundamental to cancer development and progression. They were first recognized as pro-viral integration sites for the Moloney Murine Leukemia virus. Unlike other kinases, they possess a hinge region which creates a unique binding pocket for ATP. Absence of a regulatory domain means that these proteins are constitutively active once transcribed. Pim kinases are critical downstream effectors of the ABL (ableson), JAK2 (janus kinase 2), and Flt-3 (FMS related tyrosine kinase 1) oncogenes and are required by them to drive tumorigenesis. Recent investigations have established that the Pim kinases function as effective inhibitors of apoptosis and when overexpressed, produce resistance to the mTOR (mammalian target of rapamycin) inhibitor, rapamycin . Overexpression of the PIM kinases has been reported in several hematological and solid tumors (PIM 1), myeloma, lymphoma, leukemia (PIM 2) and adenocarcinomas (PIM 3). As such, the Pim kinases are a very attractive target for pharmacological inhibition in cancer therapy. Novel small molecule inhibitors of the human Pim kinases have been designed and are currently undergoing preclinical evaluation.

Topics: Animals; Antineoplastic Agents; Drug Discovery; Humans; Imidazoles; Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-pim-1; Pyridazines; Signal Transduction

Topics: Animals; Antineoplastic Agents; Humans; Isoenzymes; Neoplasms; Protein Conformation; Proto-Oncogene Proteins c-pim-1; Signal Transduction

The PIM kinase inhibitor, SGI-1776, was tested against the PPTP in vitro (1.0 nM-10 µM) and in vivo panels (148 mg/kg daily × 5 days for 3 weeks). SGI-1776 exhibited cytotoxic activity in vitro with a median relative IC(50) of 3.1 µM. SGI-1776 induced significant differences in EFS distribution in vivo in 9 of 31 solid tumor xenografts and in 1 of 8 of the evaluable ALL xenografts. SGI-1776 induced tumor growth inhibition meeting criteria for intermediate EFS T/C activity in 1 of 39 evaluable models. In contrast, SGI-1776 induced complete responses of subcutaneous MV4;11 (B myeloid leukemia).

Topics: Adaptor Proteins, Signal Transducing; Animals; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Imidazoles; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasms; Phosphoproteins; Proto-Oncogene Proteins c-pim-1; Pyridazines; Xenograft Model Antitumor Assays