nps-1034 and Neoplasms

Dysregulation of the AXL receptor tyrosine kinase has been associated with many types of cancer. It has not been until recently, however, that targeting AXL has come under the spotlight because of ever accumulating evidence of its strong correlation with poor prognosis and drug resistance. The entry of the first AXL-branded inhibitor in clinical trials in 2013 marked an important milestone for the clinical validation of AXL as an anticancer target. Nevertheless, to weigh the current contribution and potential future impact of AXL inhibition in the clinic, it is fundamental to recognize that several kinase inhibitors approved or in clinical development have AXL as either a prominent secondary or even the primary target. Through this review, the chemical and biological properties of the main inhibitors targeting AXL (either intentionally or unintentionally) will be discussed, along with the prospects and challenges to translate AXL inhibitors into a bona fide therapeutic option.

Topics: Axl Receptor Tyrosine Kinase; Chemistry, Pharmaceutical; Humans; Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases

The MET proto-oncogene product, which is the receptor for hepatocyte growth factor (HGF), has been implicated in tumorigenesis and metastatic progression. Point mutations in MET lead to the aberrant activation of the receptor in many types of human malignancies, and the deregulated activity of MET has been correlated with tumor growth, invasion, and metastasis. MET has therefore attracted considerable attention as a potential target in anticancer therapy. Here, we report that a novel MET kinase inhibitor, NPS-1034, inhibits various constitutively active mutant forms of MET as well as HGF-activated wild-type MET. NPS-1034 inhibited the proliferation of cells expressing activated MET and promoted the regression of tumors formed from such cells in a mouse xenograft model through anti-angiogenic and pro-apoptotic actions. NPS-1034 also inhibited HGF-stimulated activation of MET signaling in the presence or absence of serum. Furthermore, when tested on 27 different MET variants, NPS-1034 inhibited 15 of the 17 MET variants that exhibited autophosphorylation with nanomolar potency; only the F1218I and M1149T variants were not inhibited by NPS-1034. Notably, NPS-1034 inhibited three MET variants that are resistant to the MET inhibitors SU11274, NVP-BVU972, and PHA665752. Together, these results suggest that NPS-1034 can be used as a potent therapeutic agent for human malignancies bearing MET point mutations or expressing activated MET.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Female; Hepatocyte Growth Factor; Heterocyclic Compounds, 2-Ring; Humans; Mice, Mutant Strains; Mutation; Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Mas; Proto-Oncogene Proteins c-met; Pyrazoles; Tumor Burden; Xenograft Model Antitumor Assays