OTSSP167 - CAS 1431697-89-0
Catalog number:
1431697-89-0
Category:
Inhibitor
Not Intended for Therapeutic Use. For research use only.
COA:
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Targets:
MELK
Description:
OTSSP167, also known as OTS167, is an orally available inhibitor of maternal embryonic leucine zipper kinase (MELK) with potential antineoplastic activity. Upon administration, OTS167 binds to MELK, which prevents both MELK phosphorylation and activation; thus inhibiting the phosphorylation of downstream MELK substrates. This may lead to an inhibition of both cell proliferation and survival in MELK-expressing tumor cells. MELK, a serine/threonine kinase, is involved in cancer cell survival, invasiveness and cancer-stem cell formation and maintenance; it is highly upregulated in various types of cancer cells and absent in normal, healthy cells.
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Purity:
0.98
Appearance:
Solid powder
Synonyms:
1-(6-(3,5-dichloro-4-hydroxyphenyl)-4-(((1r,4r)-4-((dimethylamino)methyl)cyclohexyl)amino)-1,5-naphthyridin-3-yl)ethanone; OTSSP167 free base; OTSSP 167; OTSSP-167; OTS167; OTS-167; OTS 167
MSDS:
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InChIKey:
DKZYXHCYPUVGAF-JCNLHEQBSA-N
InChI:
1S/C25H28Cl2N4O2/c1-14(32)18-12-28-22-9-8-21(16-10-19(26)25(33)20(27)11-16)30-24(22)23(18)29-17-6-4-15(5-7-17)13-31(2)3/h8-12,15,17,33H,4-7,13H2,1-3H3,(H,28,29)/t15-,17-
Canonical SMILES:
CC(C1=C(N[C@H]2CC[C@H](CN(C)C)CC2)C3=NC(C4=CC(Cl)=C(O)C(Cl)=C4)=CC=C3N=C1)=O
1.OTSSP167 Abrogates Mitotic Checkpoint through Inhibiting Multiple Mitotic Kinases.
Ji W1, Arnst C1, Tipton AR1, Bekier ME 2nd1, Taylor WR1, Yen TJ2, Liu ST1. PLoS One. 2016 Apr 15;11(4):e0153518. doi: 10.1371/journal.pone.0153518. eCollection 2016.
OTSSP167 was recently characterized as a potent inhibitor for maternal embryonic leucine zipper kinase (MELK) and is currently tested in Phase I clinical trials for solid tumors that have not responded to other treatment. Here we report that OTSSP167 abrogates the mitotic checkpoint at concentrations used to inhibit MELK. The abrogation is not recapitulated by RNAi mediated silencing of MELK in cells. Although OTSSP167 indeed inhibits MELK, it exhibits off-target activity against Aurora B kinase in vitro and in cells. Furthermore, OTSSP167 inhibits BUB1 and Haspin kinases, reducing phosphorylation at histones H2AT120 and H3T3 and causing mislocalization of Aurora B and associated chromosomal passenger complex from the centromere/kinetochore. The results suggest that OTSSP167 may have additional mechanisms of action for cancer cell killing and caution the use of OTSSP167 as a MELK specific kinase inhibitor in biochemical and cellular assays.
2.The crystal structure of MPK38 in complex with OTSSP167, an orally administrative MELK selective inhibitor.
Cho YS1, Kang Y1, Kim K1, Cha YJ1, Cho HS2. Biochem Biophys Res Commun. 2014 Apr 25;447(1):7-11. doi: 10.1016/j.bbrc.2014.03.034. Epub 2014 Mar 18.
Murine protein serine/threonine kinase 38 (MPK38), also known as maternal embryonic leucine zipper kinase (MELK), has been associated with various human cancers and plays an important role in the formation of cancer stem cells. OTSSP167, a MELK selective inhibitor, exhibits a strong in vitro activity, conferring an IC50 of 0.41nM and in vivo effect on various human cancer xenograft models. Here, we report the crystal structure of MPK38 (T167E), an active mutant, in complex with OTSSP167 and describe its detailed protein-inhibitor interactions. Comparison with the previous determined structure of MELK bound to the nanomolar inhibitors shows that OTSSP167 effectively fits into the active site, thus offering an opportunity for structure-based development and optimization of MELK inhibitors.
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CAS 1431697-89-0 OTSSP167

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(CAS: 1431697-89-0)

OTSSP167, also known as OTS167, is an orally available inhibitor of maternal embryonic leucine zipper kinase (MELK) with potential antineoplastic activity. Upo...

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CAS 1431697-89-0 OTSSP167

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