NVP-BVU972

NVP-BVU972 is a selective and potent inhibitor of c-Met with IC50 of 14 nM. Besides, NVP-BVU972 displays IC50 values more than 1000 nM in other kinases such as the most closely related kinase recepteur d'origine nantais (RON).

c-Met, also known as hepatocyte growth factor receptor, is a receptor tyrosine kinase that can be activated by hepatocyte growth factor/scatter factor (HGF/SF). It is a membrane protein which plays an essential role in embryonic development and wound healing.

In the EBC-1, GTL-16, and MKN-45 human cancer cells, NVP-BVU972 potently inhibits the cell proliferation with IC50 values of 82, 66 and 32 nM, respectively. Additionally, NVP-BVU972 treatment leads to the inhibition of the growth of the transformed mouse BaF3 cells containing TPR-MET kinase fusions with IC50 of 104 nM 1.

In human sample, NVP-BVU972 treatment on cells expressing wild-type TPR-MET resulted in a dose-dependent reduction in TPR-MET phosphorylation. Y1230H, D1228A, F1200I and L1195V mutations abrogate the TPR-MET phosphorylation inhibition effect of NVP-BVU972 in BaF3 TPR-MET1.

Reference:
1.   Tiedt R, Degenkolbe E, Furet P, et al. A drug resistance screen using a selective MET inhibitor reveals a spectrum of mutations that partially overlap with activating mutations found in cancer patients. Cancer research. 2011;71(15):5255-5264.

A drug resistance screen using a selective MET inhibitor reveals a spectrum of mutations that partially overlap with activating mutations found in cancer patients.[Pubmed:21697284]

Cancer Res. 2011 Aug 1;71(15):5255-64.

The emergence of drug resistance is a primary concern in any cancer treatment, including with targeted kinase inhibitors as exemplified by the appearance of Bcr-Abl point mutations in chronic myeloid leukemia (CML) patients treated with imatinib. In vitro approaches to identify resistance mutations in Bcr-Abl have yielded mutation spectra that faithfully recapitulated clinical observations. To predict resistance mutations in the receptor tyrosine kinase MET that could emerge during inhibitor treatment in patients, we conducted a resistance screen in BaF3 TPR-MET cells using the novel selective MET inhibitor NVP-BVU972. The observed spectrum of mutations in resistant cells was dominated by substitutions of tyrosine 1230 but also included other missense mutations and partially overlapped with activating MET mutations that were previously described in cancer patients. Cocrystallization of the MET kinase domain in complex with NVP-BVU972 revealed a key role for Y1230 in binding of NVP-BVU972, as previously reported for multiple other selective MET inhibitors. A second resistance screen in the same format with the MET inhibitor AMG 458 yielded a distinct spectrum of mutations rich in F1200 alterations, which is consistent with a different predicted binding mode. Our findings suggest that amino acid substitutions in the MET kinase domain of cancer patients need to be carefully monitored before and during treatment with MET inhibitors, as resistance may preexist or emerge. Compounds binding in the same manner as NVP-BVU972 might be particularly susceptible to the development of resistance through mutations in Y1230, a condition that may be addressed by MET inhibitors with alternative binding modes.

NPS-1034, a novel MET inhibitor, inhibits the activated MET receptor and its constitutively active mutants.[Pubmed:24173966]

Invest New Drugs. 2014 Jun;32(3):389-99.

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.