000135892 001__ 135892
000135892 005__ 20240627150548.0
000135892 0247_ $$2doi$$a10.3390/biom11101453
000135892 0248_ $$2sideral$$a125274
000135892 037__ $$aART-2021-125274
000135892 041__ $$aeng
000135892 100__ $$aRizzuti, Bruno
000135892 245__ $$aDesign of Inhibitors of the Intrinsically Disordered Protein NUPR1: Balance between Drug Affinity and Target Function
000135892 260__ $$c2021
000135892 5060_ $$aAccess copy available to the general public$$fUnrestricted
000135892 5203_ $$aIntrinsically disordered proteins (IDPs) are emerging as attractive drug targets by virtue of their physiological ubiquity and their prevalence in various diseases, including cancer. NUPR1 is an IDP that localizes throughout the whole cell, and is involved in the development and progression of several tumors. We have previously repurposed trifluoperazine (TFP) as a drug targeting NUPR1 and, by using a ligand-based approach, designed the drug ZZW-115 starting from the TFP scaffold. Such derivative compound hinders the development of pancreatic ductal adenocarcinoma (PDAC) in mice, by hampering nuclear translocation of NUPR1. Aiming to further improve the activity of ZZW-115, here we have used an indirect drug design approach to modify its chemical features, by changing the substituent attached to the piperazine ring. As a result, we have synthesized a series of compounds based on the same chemical scaffold. Isothermal titration calorimetry (ITC) showed that, with the exception of the compound preserving the same chemical moiety at the end of the alkyl chain as ZZW-115, an increase of the length by a single methylene group (i.e., ethyl to propyl) significantly decreased the affinity towards NUPR1 measured in vitro, whereas maintaining the same length of the alkyl chain and adding heterocycles favored the binding affinity. However, small improvements of the compound affinity towards NUPR1, as measured by ITC, did not result in a corresponding improvement in their inhibitory properties and in cellulo functions, as proved by measuring three different biological effects: hindrance of the nuclear translocation of the protein, sensitization of cells against DNA damage mediated by NUPR1, and prevention of cancer cell growth. Our findings suggest that a delicate compromise between favoring ligand affinity and controlling protein function may be required to successfully design drugs against NUPR1, and likely other IDPs.
000135892 536__ $$9info:eu-repo/grantAgreement/ES/DGA/B25-20R$$9info:eu-repo/grantAgreement/ES/DGA/E45-20R$$9info:eu-repo/grantAgreement/ES/ISCIII-FIS/PI18-00349$$9info:eu-repo/grantAgreement/ES/MCIU-AEI-FEDER/RTI2018-097991-B-I00
000135892 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000135892 590__ $$a6.064$$b2021
000135892 591__ $$aBIOCHEMISTRY & MOLECULAR BIOLOGY$$b75 / 297 = 0.253$$c2021$$dQ2$$eT1
000135892 592__ $$a1.019$$b2021
000135892 593__ $$aMolecular Biology$$c2021$$dQ2
000135892 593__ $$aBiochemistry$$c2021$$dQ2
000135892 594__ $$a5.7$$b2021
000135892 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000135892 700__ $$aLan, Wenjun
000135892 700__ $$aSantofimia-Castaño, Patricia
000135892 700__ $$aZhou, Zhengwei
000135892 700__ $$0(orcid)0000-0001-5702-4538$$aVelázquez-Campoy, Adrián$$uUniversidad de Zaragoza
000135892 700__ $$0(orcid)0000-0001-5664-1729$$aAbián, Olga$$uUniversidad de Zaragoza
000135892 700__ $$aPeng, Ling
000135892 700__ $$aNeira, José L.
000135892 700__ $$aXia, Yi
000135892 700__ $$aIovanna, Juan L.
000135892 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000135892 773__ $$g11, 10 (2021), 1453 [19 pp.]$$tBiomolecules$$x2218-273X
000135892 8564_ $$s1750724$$uhttps://zaguan.unizar.es/record/135892/files/texto_completo.pdf$$yVersión publicada
000135892 8564_ $$s2830195$$uhttps://zaguan.unizar.es/record/135892/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000135892 909CO $$ooai:zaguan.unizar.es:135892$$particulos$$pdriver
000135892 951__ $$a2024-06-27-13:20:09
000135892 980__ $$aARTICLE