Reference Detail

Ref Type Journal Article
PMID (22440753)
Authors Waaler J, Machon O, Tumova L, Dinh H, Korinek V, Wilson SR, Paulsen JE, Pedersen NM, Eide TJ, Machonova O, Gradl D, Voronkov A, von Kries JP, Krauss S
Title A novel tankyrase inhibitor decreases canonical Wnt signaling in colon carcinoma cells and reduces tumor growth in conditional APC mutant mice.
Journal Cancer research
Vol 72
Issue 11
Date 2012 Jun 01
URL
Abstract Text Increased nuclear accumulation of β-catenin, a mediator of canonical Wnt signaling, is found in numerous tumors and is frequently associated with tumor progression and metastasis. Inhibition of Wnt/β-catenin signaling therefore is an attractive strategy for anticancer drugs. In this study, we have identified a novel small molecule inhibitor of the β-catenin signaling pathway, JW55, that functions via inhibition of the PARP domain of tankyrase 1 and tankyrase 2 (TNKS1/2), regulators of the β-catenin destruction complex. Inhibition of TNKS1/2 poly(ADP-ribosyl)ation activity by JW55 led to stabilization of AXIN2, a member of the β-catenin destruction complex, followed by increased degradation of β-catenin. In a dose-dependent manner, JW55 inhibited canonical Wnt signaling in colon carcinoma cells that contained mutations in either the APC (adenomatous polyposis coli) locus or in an allele of β-catenin. In addition, JW55 reduced XWnt8-induced axis duplication in Xenopus embryos and tamoxifen-induced polyposis formation in conditional APC mutant mice. Together, our findings provide a novel chemotype for targeting canonical Wnt/β-catenin signaling through inhibiting the PARP domain of TNKS1/2.

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Molecular Profile Treatment Approach
APC I1557fs Tankyrase Inhibitor
APC S1346* Tankyrase Inhibitor
APC Q1367* Tankyrase Inhibitor
APC D1394fs Tankyrase Inhibitor
CTNNB1 S33P Tankyrase Inhibitor
APC A1492fs Tankyrase Inhibitor
APC P1483fs Tankyrase Inhibitor
APC R564* Tankyrase Inhibitor
CTNNB1 S45P Tankyrase Inhibitor
CTNNB1 D32G Tankyrase Inhibitor
APC E1464* Tankyrase Inhibitor
APC A952Qfs*10 Tankyrase Inhibitor
APC K1310fs Tankyrase Inhibitor
APC E868* Tankyrase Inhibitor
CTNNB1 S33T Tankyrase Inhibitor
APC D1318fs Tankyrase Inhibitor
APC A1402fs Tankyrase Inhibitor
APC L1488* Tankyrase Inhibitor
APC E1322* Tankyrase Inhibitor
APC N1026S Tankyrase Inhibitor
APC H1490fs Tankyrase Inhibitor
CTNNB1 A21T Tankyrase Inhibitor
CTNNB1 G48D Tankyrase Inhibitor
APC C1410* Tankyrase Inhibitor
APC E1552* Tankyrase Inhibitor
APC E1544* Tankyrase Inhibitor
CTNNB1 D32Y Tankyrase Inhibitor
CTNNB1 N387K Tankyrase Inhibitor
CTNNB1 A39T Tankyrase Inhibitor
APC P1373fs Tankyrase Inhibitor
APC E1309fs Tankyrase Inhibitor
APC Y737* Tankyrase Inhibitor
APC Q1294fs Tankyrase Inhibitor
APC R302* Tankyrase Inhibitor
APC E1577* Tankyrase Inhibitor
APC E1464fs Tankyrase Inhibitor
APC I1307Kfs*14 Tankyrase Inhibitor
APC R1114* Tankyrase Inhibitor
APC Y1376* Tankyrase Inhibitor
APC L684* Tankyrase Inhibitor
CTNNB1 D32E Tankyrase Inhibitor
APC A1351fs Tankyrase Inhibitor
APC I606fs Tankyrase Inhibitor
CTNNB1 A43P Tankyrase Inhibitor
APC A1296fs Tankyrase Inhibitor
CTNNB1 S37C Tankyrase Inhibitor
APC E1554* Tankyrase Inhibitor
APC R1435* Tankyrase Inhibitor
APC S1411fs Tankyrase Inhibitor
APC E1306fs Tankyrase Inhibitor
CTNNB1 S45N Tankyrase Inhibitor
APC R1450* Tankyrase Inhibitor
CTNNB1 D32A Tankyrase Inhibitor
APC A1446fs Tankyrase Inhibitor
CTNNB1 G34E Tankyrase Inhibitor
APC I1311fs Tankyrase Inhibitor
APC N1300fs Tankyrase Inhibitor
APC R232* Tankyrase Inhibitor
APC K1555fs Tankyrase Inhibitor
APC inact mut Tankyrase Inhibitor
APC A1475fs Tankyrase Inhibitor
APC S1278* Tankyrase Inhibitor
APC P1439fs Tankyrase Inhibitor
APC E1374* Tankyrase Inhibitor
CTNNB1 D32N Tankyrase Inhibitor
APC P950Afs*13 Tankyrase Inhibitor
APC E853* Tankyrase Inhibitor
APC E1451* Tankyrase Inhibitor
APC T1301Pfs*4 Tankyrase Inhibitor
APC E1345* Tankyrase Inhibitor
APC D1484fs Tankyrase Inhibitor
CTNNB1 G34A Tankyrase Inhibitor
APC E1379* Tankyrase Inhibitor
APC S1436fs Tankyrase Inhibitor
APC Q1447* Tankyrase Inhibitor
CTNNB1 E54K Tankyrase Inhibitor
APC G1312fs Tankyrase Inhibitor
APC R216* Tankyrase Inhibitor
APC P1372fs Tankyrase Inhibitor
APC P1497fs Tankyrase Inhibitor
CTNNB1 S45A Tankyrase Inhibitor
APC E658* Tankyrase Inhibitor
APC Q1378* Tankyrase Inhibitor
APC A1470fs Tankyrase Inhibitor
CTNNB1 S45T Tankyrase Inhibitor
APC E1554fs Tankyrase Inhibitor
APC I1307fs Tankyrase Inhibitor
APC E1295* Tankyrase Inhibitor
APC I1164fs Tankyrase Inhibitor
APC R1435fs Tankyrase Inhibitor
APC L665* Tankyrase Inhibitor
APC R1314fs Tankyrase Inhibitor
APC S31fs Tankyrase Inhibitor
APC A1485fs Tankyrase Inhibitor
CTNNB1 S45Y Tankyrase Inhibitor
CTNNB1 H36Y Tankyrase Inhibitor
APC S1400* Tankyrase Inhibitor
CTNNB1 S45del Tankyrase Inhibitor
APC R405* Tankyrase Inhibitor
APC E1408* Tankyrase Inhibitor
APC R213* Tankyrase Inhibitor
APC G1416* Tankyrase Inhibitor
APC E1309Dfs*4 Tankyrase Inhibitor
CTNNB1 G38P Tankyrase Inhibitor
CTNNB1 S37P Tankyrase Inhibitor
APC K1462fs Tankyrase Inhibitor
APC Q1303fs Tankyrase Inhibitor
APC D1486fs Tankyrase Inhibitor
APC Q1378fs Tankyrase Inhibitor
APC Q1480* Tankyrase Inhibitor
APC R554* Tankyrase Inhibitor
CTNNB1 G34V Tankyrase Inhibitor
APC A1305fs Tankyrase Inhibitor
APC P1361fs Tankyrase Inhibitor
APC R876* Tankyrase Inhibitor
APC N741fs Tankyrase Inhibitor
CTNNB1 E67K Tankyrase Inhibitor
APC S1355fs Tankyrase Inhibitor
APC A928fs Tankyrase Inhibitor
APC S1364fs Tankyrase Inhibitor
APC S1315* Tankyrase Inhibitor
APC E1306* Tankyrase Inhibitor
CTNNB1 A43T Tankyrase Inhibitor
CTNNB1 D32H Tankyrase Inhibitor
APC K1310* Tankyrase Inhibitor
APC S1215* Tankyrase Inhibitor
APC R283* Tankyrase Inhibitor
APC S1465fs Tankyrase Inhibitor
APC P1458fs Tankyrase Inhibitor
APC P1319fs Tankyrase Inhibitor
APC S1495fs Tankyrase Inhibitor
APC A1325fs Tankyrase Inhibitor
APC C1387* Tankyrase Inhibitor
APC K716* Tankyrase Inhibitor
APC P1443fs Tankyrase Inhibitor
CTNNB1 S37T Tankyrase Inhibitor
APC T1438fs Tankyrase Inhibitor
APC E1494fs Tankyrase Inhibitor
APC R499* Tankyrase Inhibitor
CTNNB1 A13T Tankyrase Inhibitor
CTNNB1 S37A Tankyrase Inhibitor
CTNNB1 act mut Tankyrase Inhibitor
CTNNB1 P44A Tankyrase Inhibitor
APC H1375fs Tankyrase Inhibitor
APC Q1303* Tankyrase Inhibitor
APC N869fs Tankyrase Inhibitor
APC L1489fs Tankyrase Inhibitor
APC T1496fs Tankyrase Inhibitor
APC L1564* Tankyrase Inhibitor
APC E1461* Tankyrase Inhibitor
APC R1399Ffs*9 Tankyrase Inhibitor
CTNNB1 S33Y Tankyrase Inhibitor
APC P1440fs Tankyrase Inhibitor
APC K1555* Tankyrase Inhibitor
APC Q1429* Tankyrase Inhibitor
APC R640G Tankyrase Inhibitor
APC Q424* Tankyrase Inhibitor
APC G1499* Tankyrase Inhibitor
CTNNB1 S45F Tankyrase Inhibitor
APC E1309Afs*3 Tankyrase Inhibitor
APC E1317* Tankyrase Inhibitor
APC K1817fs Tankyrase Inhibitor
APC G471* Tankyrase Inhibitor
CTNNB1 I35S Tankyrase Inhibitor
APC C1274fs Tankyrase Inhibitor
APC D1297fs Tankyrase Inhibitor
APC R1348fs Tankyrase Inhibitor
APC S811* Tankyrase Inhibitor
APC Q1338* Tankyrase Inhibitor
CTNNB1 H36P Tankyrase Inhibitor
APC C207* Tankyrase Inhibitor
APC S1315fs Tankyrase Inhibitor
APC M1525Lfs*39 Tankyrase Inhibitor
APC Y935* Tankyrase Inhibitor
APC K1350* Tankyrase Inhibitor
CTNNB1 S37F Tankyrase Inhibitor
APC E1513* Tankyrase Inhibitor
APC N1455fs Tankyrase Inhibitor
CTNNB1 S45C Tankyrase Inhibitor
APC L1488Ffs*26 Tankyrase Inhibitor
APC S1465Wfs*3 Tankyrase Inhibitor
APC Q1131* Tankyrase Inhibitor
APC A1316fs Tankyrase Inhibitor
CTNNB1 W25_D32del Tankyrase Inhibitor
APC Q1096* Tankyrase Inhibitor
APC P1453fs Tankyrase Inhibitor
CTNNB1 G34R Tankyrase Inhibitor
CTNNB1 V22A Tankyrase Inhibitor
APC C1387fs Tankyrase Inhibitor
CTNNB1 T41I Tankyrase Inhibitor
APC L795Sfs*25 Tankyrase Inhibitor
APC T1459fs Tankyrase Inhibitor
CTNNB1 S33F Tankyrase Inhibitor
APC G1312* Tankyrase Inhibitor
CTNNB1 K335I Tankyrase Inhibitor
CTNNB1 S33A Tankyrase Inhibitor
APC S1356fs Tankyrase Inhibitor
APC T1493fs Tankyrase Inhibitor
APC Y1376fs Tankyrase Inhibitor
APC T1556fs Tankyrase Inhibitor
APC Q1444* Tankyrase Inhibitor
APC E1397* Tankyrase Inhibitor
CTNNB1 T41A Tankyrase Inhibitor
APC C1578fs Tankyrase Inhibitor
CTNNB1 A39G Tankyrase Inhibitor
APC G1357fs Tankyrase Inhibitor
APC F1491fs Tankyrase Inhibitor
APC Q1294* Tankyrase Inhibitor
APC Q1406* Tankyrase Inhibitor
CTNNB1 I35T Tankyrase Inhibitor
APC S1197* Tankyrase Inhibitor
APC Q886* Tankyrase Inhibitor
APC E1309* Tankyrase Inhibitor
APC P1443Lfs*30 Tankyrase Inhibitor
CTNNB1 S33C Tankyrase Inhibitor
CTNNB1 S33L Tankyrase Inhibitor
APC K1308* Tankyrase Inhibitor
APC T1445fs Tankyrase Inhibitor
APC L1488fs Tankyrase Inhibitor
APC T1301fs Tankyrase Inhibitor
APC Q1469* Tankyrase Inhibitor
APC A1471fs Tankyrase Inhibitor
APC Q1067* Tankyrase Inhibitor
APC D1422fs Tankyrase Inhibitor
APC E190* Tankyrase Inhibitor
APC E763* Tankyrase Inhibitor
APC C1289fs Tankyrase Inhibitor
APC F1354fs Tankyrase Inhibitor
APC Q1127* Tankyrase Inhibitor
APC T621Lfs*9 Tankyrase Inhibitor
APC K1370* Tankyrase Inhibitor
APC W553* Tankyrase Inhibitor
CTNNB1 S37Y Tankyrase Inhibitor
CTNNB1 P44_S45del Tankyrase Inhibitor
APC Q1291* Tankyrase Inhibitor
APC M1431fs Tankyrase Inhibitor
APC K1449fs Tankyrase Inhibitor
APC S1356* Tankyrase Inhibitor
APC E1547* Tankyrase Inhibitor
APC W421* Tankyrase Inhibitor
APC N1455Ifs*18 Tankyrase Inhibitor
CTNNB1 S33N Tankyrase Inhibitor
APC D1425fs Tankyrase Inhibitor
CTNNB1 D32V Tankyrase Inhibitor
CTNNB1 W383R Tankyrase Inhibitor
CTNNB1 I35N Tankyrase Inhibitor
APC E1353* Tankyrase Inhibitor
APC V1377fs Tankyrase Inhibitor
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
JW55 JW55 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
JW55 Tankyrase Inhibitor 9 JW55 selectively inhibits Wnt/beta-catenin-mediated signaling by inhibiting tankyrase1/2, thus stabilizing axin and stimulating beta-catenin degradation, which prevents cell division and decreases tumor growth (PMID: 22440753).
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
APC inact mut colon cancer sensitive JW55 Preclinical Actionable In a preclinical study, JW55 inhibited proliferation of colorectal cancer cells with an APC truncation mutation in culture and decreased tumor development in a mouse model expressing a conditional APC truncation mutation (PMID: 22440753). 22440753