NVP-BVU972 - CAS 1185763-69-2
Catalog number: 1185763-69-2
Category: Inhibitor
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Molecular Formula:
C20H16N6
Molecular Weight:
340.38
COA:
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Targets:
c-Met/HGFR
Description:
NVP-BVU972 potently inhibits MET kinase but displays low inhibition against other kinases including the most closely related kinase RON with IC50 values of more than 1000 nM.
Purity:
>98%
Synonyms:
NVP BVU972; NVPBVU972; NVP-BVU972; BVU-972; BVU 972; BVU972
MSDS:
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InChIKey:
RNCNPRCUHHDYPC-UHFFFAOYSA-N
InChI:
InChI=1S/C20H16N6/c1-25-13-16(11-23-25)19-6-7-20-22-12-17(26(20)24-19)10-14-4-5-18-15(9-14)3-2-8-21-18/h2-9,11-13H,10H2,1H3
Canonical SMILES:
CN1C=C(C=N1)C2=NN3C(=NC=C3CC4=CC5=C(C=C4)N=CC=C5)C=C2
1.NPS-1034, a novel MET inhibitor, inhibits the activated MET receptor and its constitutively active mutants.
Shin JS;Hong SW;Moon JH;Kim JS;Jung KA;Kim SM;Lee DH;Kim I;Yoon SJ;Lee CG;Choi EK;Lee JY;Kim KP;Hong YS;Lee JL;Kim B;Choi EK;Lee JS;Jin DH;Kim TW Invest New Drugs. 2014 Jun;32(3):389-99. doi: 10.1007/s10637-013-0039-4. Epub 2013 Oct 31.
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.
2.Crystal structure of 1,3-bis-(1H-benzotriazol-1-yl-meth-yl)benzene.
Macías MA;Nuñez-Dallos N;Hurtado J;Suescun L Acta Crystallogr E Crystallogr Commun. 2016 May 17;72(Pt 6):815-8. doi: 10.1107/S2056989016007805. eCollection 2016 Jun 1.
The mol-ecular structure of the title compound, C20H16N6, contains two benzotriazole units bonded to a benzene nucleus in a meta configuration, forming dihedral angles of 88.74 (11) and 85.83 (10)° with the central aromatic ring and 57.08 (9)° with each other. The three-dimensional structure is controlled mainly by weak C-H⋯N and C-H⋯π inter-actions. The mol-ecules are connected in inversion-related pairs, forming the slabs of infinite chains that run along the [-110] and [110] directions.
3.A drug resistance screen using a selective MET inhibitor reveals a spectrum of mutations that partially overlap with activating mutations found in cancer patients.
Tiedt R;Degenkolbe E;Furet P;Appleton BA;Wagner S;Schoepfer J;Buck E;Ruddy DA;Monahan JE;Jones MD;Blank J;Haasen D;Drueckes P;Wartmann M;McCarthy C;Sellers WR;Hofmann F Cancer Res. 2011 Aug 1;71(15):5255-64. doi: 10.1158/0008-5472.CAN-10-4433. Epub 2011 Jun 22.
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.
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CAS 1185763-69-2 NVP-BVU972

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