Super-TDU is a rationally designed peptide-based inhibitor targeting the YAP-TEADs interaction by mimicking the VGLL with anticancer activity. VGLL4 is a previously identified YAP antagonist which also functions as a regulator of Wnt/β-catenin signalling. Super-TDU demonstrated therapeutic potentials for treating human cancer with YAP-activation. It reduced endogenous interaction between YAP and TEADs as shown by coIP experiment. Super-TDU inhibited cell viability and colony formation of GC cell lines MGC-803, BGC-823, and HGC27, but not MKN-45 as predicted. Moreover, the Super-TDU downregulated expression of YAP-TEADs target genes CTGF, CYR61, and CDX2. Further chromatin immunoprecipitation (ChIP) assays also showed that the Super-TDU dose-dependently reduced the amount of CTGF and CDX2 promoter cDNA ChIPed by YAP antibody. To verify the specificity of the Super-TDU, two Super-TDU mutants were created which harbor mutations that disable TEADs binding. As expected, the mutant Super-TDUs failed to interact with TEADs and inhibit cell proliferation. Thus the Super-TDU appears to have a broad but specific antitumor activity toward YAP-driven human cancers in which YAP/VGLL4 ratio should be considered as an important prognostic marker for personalized treatment.
Physicochemical Properties
| Molecular Formula | C237H370N66O69S | |
| Molecular Weight | 5279.9396 | |
| Exact Mass | 5278.726 | |
| CAS # | 1599441-71-0 | |
| Related CAS # | Super-TDU TFA | |
| PubChem CID | 155886330 | |
| Appearance | White to off-white solid powder | |
| LogP | -25.5 | |
| Hydrogen Bond Donor Count | 71 | |
| Hydrogen Bond Acceptor Count | 81 | |
| Rotatable Bond Count | 173 | |
| Heavy Atom Count | 373 | |
| Complexity | 13400 | |
| Defined Atom Stereocenter Count | 0 | |
| SMILES | S(C)CCC(C(NC(C(NC(C(NC(CCCNC(=N)N)C(NC(CCCCN)C(NC(CC(C)C)C(N1CCCC1C(NC(CC(=O)O)C(NC(CO)C(NC(CC1C=CC=CC=1)C(NC(CC1C=CC=CC=1)C(NC(CCCCN)C(N1CCCC1C(N1CCCC1C(NC(C(N)=O)CCC(=O)O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)CC(C)C)=O)CCCNC(=N)N)=O)NC(C1CCCN1C(C(C(C)C)NC(C(C(C)O)NNC(CCC(N)=O)C(C(C1CCCN1C(C(C(C)C)NC(C(CC(N)=O)NC(C(C)NC(C(C(C)O)NC(C(CCCCN)NC(C1CCCN1C(C(CC(N)=O)NC(CNC(C(CO)NC(CNC(CNC(C(C(C)CC)NC(C(CCC(N)=O)NC(C(CC(C)C)NC(C(CC1=CNC2=CC=CC=C12)NC(C(C(C)O)NC(C(CC(=O)O)NC(CNC(C(CC(C)C)NC(C(CO)NC(C(CCCCN)NC(C(C)NC(C(CC1C=CC=CC=1)NC(C(CC1=CN=CN1)NC(C(CC(=O)O)NC(C(CC(=O)O)NC(C(C(C)C)NNC(C=O)CO)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O |
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| InChi Key | VNAMPXYTTUOEFP-UHFFFAOYSA-N | |
| InChi Code | InChI=1S/C237H370N66O69S/c1-23-125(16)189(291-206(343)146(72-75-174(243)313)270-209(346)151(93-120(6)7)277-212(349)155(98-134-106-254-138-58-34-33-57-137(134)138)284-228(365)191(129(20)310)293-218(355)158(102-182(322)323)262-179(318)110-256-198(335)149(91-118(2)3)275-219(356)165(115-307)287-203(340)141(59-35-39-78-238)266-196(333)126(17)260-207(344)152(95-131-51-27-24-28-52-131)278-213(350)156(99-135-107-251-117-259-135)281-214(351)159(103-183(324)325)282-215(352)161(105-185(328)329)285-226(363)186(122(10)11)296-294-136(112-304)113-305)225(362)258-108-177(316)255-109-178(317)264-164(114-306)199(336)257-111-180(319)263-163(101-176(245)315)232(369)300-86-46-66-168(300)222(359)271-143(61-37-41-80-240)205(342)292-190(128(19)309)227(364)261-127(18)197(334)274-157(100-175(244)314)217(354)289-187(123(12)13)234(371)298-84-45-65-167(298)194(331)193(330)139(71-74-173(242)312)295-297-192(130(21)311)229(366)290-188(124(14)15)235(372)302-88-49-69-171(302)223(360)272-147(77-90-373-22)204(341)268-145(64-44-83-253-237(249)250)201(338)276-150(92-119(4)5)208(345)269-144(63-43-82-252-236(247)248)200(337)267-142(60-36-40-79-239)202(339)286-162(94-121(8)9)231(368)299-85-47-67-169(299)224(361)283-160(104-184(326)327)216(353)288-166(116-308)220(357)280-154(97-133-55-31-26-32-56-133)211(348)279-153(96-132-53-29-25-30-54-132)210(347)273-148(62-38-42-81-241)230(367)303-89-50-70-172(303)233(370)301-87-48-68-170(301)221(358)265-140(195(246)332)73-76-181(320)321/h24-34,51-58,106-107,112,117-130,136,139-172,186-192,254,294-297,305-311H,23,35-50,59-105,108-111,113-116,238-241H2,1-22H3,(H2,242,312)(H2,243,313)(H2,244,314)(H2,245,315)(H2,246,332)(H,251,259)(H,255,316)(H,256,335)(H,257,336)(H,258,362)(H,260,344)(H,261,364)(H,262,318)(H,263,319)(H,264,317)(H,265,358)(H,266,333)(H,267,337)(H,268,341)(H,269,345)(H,270,346)(H,271,359)(H,272,360)(H,273,347)(H,274,334)(H,275,356)(H,276,338)(H,277,349)(H,278,350)(H,279,348)(H,280,357)(H,281,351)(H,282,352)(H,283,361)(H,284,365)(H,285,363)(H,286,339)(H,287,340)(H,288,353)(H,289,354)(H,290,366)(H,291,343)(H,292,342)(H,293,355)(H,320,321)(H,322,323)(H,324,325)(H,326,327)(H,328,329)(H4,247,248,252)(H4,249,250,253) | |
| Chemical Name | 5-amino-4-[[1-[1-[6-amino-2-[[2-[[2-[[2-[[2-[[1-[2-[[6-amino-2-[[2-[[2-[[2-[[2-[[1-[2-[[2-[2-[6-amino-1-[1-[2-[[4-amino-2-[2-[[2-[[6-amino-2-[[1-[4-amino-2-[[2-[[2-[[2-[[2-[[2-[[5-amino-2-[[2-[[2-[[2-[[2-[[2-[[2-[[2-[[6-amino-2-[2-[[2-[[2-[[3-carboxy-2-[[3-carboxy-2-[[2-[2-(1-hydroxy-3-oxopropan-2-yl)hydrazinyl]-3-methylbutanoyl]amino]propanoyl]amino]propanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-3-phenylpropanoyl]amino]propanoylamino]hexanoyl]amino]-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-carboxypropanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-methylpentanoyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]amino]acetyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]acetyl]amino]-4-oxobutanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]amino]-3-hydroxybutanoyl]amino]propanoylamino]-4-oxobutanoyl]amino]-3-methylbutanoyl]pyrrolidin-2-yl]-1,2,6-trioxohexan-3-yl]hydrazinyl]-3-hydroxybutanoyl]amino]-3-methylbutanoyl]pyrrolidine-2-carbonyl]amino]-4-methylsulfanylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-4-methylpentanoyl]amino]-5-carbamimidamidopentanoyl]amino]hexanoyl]amino]-4-methylpentanoyl]pyrrolidine-2-carbonyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]hexanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoic acid | |
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| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ln Vitro | Super-TDU inhibits the expression of CTGF, CYR61, and CDX2, the target genes of YAP-TEADs. GC cell lines MGC-803, BGC-823, and HGC27 exhibit reduced colony formation and cell survival when exposed to Super-TDU [1]. |
| ln Vivo | Super-TDU, administered intravenously once a day at doses of 50 μg/kg or 500 μg/kg, greatly lowers the size, weight, and YAP target genes of mice tumors [1]. The CLs for Super-TDU (iv; 250 μg/kg and 500 μg/kg) mice are 7.41 mL/min/kg and 7.72 mL/min/kg, respectively; Cmax values are 6.12 ng/mL and 13.3 ng/mL. The t1/2α for the mice is 0.78 hours and 0.82 hours, respectively[1]. |
| Animal Protocol |
Animal/Disease Models: BALB/cA nu/nu (nude) mice[1] Doses: 50 μg/kg or 500 μg/kg Route of Administration: intravenous (iv) Injection; per day Experimental Results: diminished the sizes, weights of tumors, and YAP target genes in a dose-dependent manner. Animal/Disease Models: BALB/cA nu/nu (nude) mice[1] Doses: 250 μg/kg or 500 μg/kg (pharmacokinetic/PK Study) Route of Administration: intravenous (iv) Injection Experimental Results: The t1/2α is 0.78 hrs (hours) and 0.82 hrs (hours); the Cmax is 6.12 ng/mL and 13.3 ng/mL; the CL is7.41 ml/min/kg and 7.72 ml/min/kg for 250 μg/kg and 500 μg/kg in mice, respectively. |
| References |
[1]. A peptide mimicking VGLL4 function acts as a YAP antagonist therapy against gastric cancer. Cancer Cell. 2014 Feb 10;25(2):166-80. |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 25 mg/mL (4.73 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.1894 mL | 0.9470 mL | 1.8940 mL | |
| 5 mM | 0.0379 mL | 0.1894 mL | 0.3788 mL | |
| 10 mM | 0.0189 mL | 0.0947 mL | 0.1894 mL |