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dc.creatorKoravović, Mladen
dc.creatorMayasundari, Anand
dc.creatorTasić, Gordana
dc.creatorKeramatnia, F.
dc.creatorStachowski, Timothy R.
dc.creatorCui, Huarui
dc.creatorChai, Sergio C.
dc.creatorJonchere, Barbara
dc.creatorYang, Lei
dc.creatorLi, Yong
dc.creatorFu, Xiang
dc.creatorHiltenbrand, Ryan
dc.creatorPaul, Leena
dc.creatorMishra, Vibhor
dc.creatorKlco, Jeffery M.
dc.creatorRoussel, Martine F.
dc.creatorPomerantz, William CK.
dc.creatorFischer, Marcus
dc.creatorRanković, Zoran
dc.creatorSavić, Vladimir
dc.date.accessioned2023-03-14T14:45:20Z
dc.date.available2023-03-14T14:45:20Z
dc.date.issued2023
dc.identifier.issn0223-5234
dc.identifier.urihttps://farfar.pharmacy.bg.ac.rs/handle/123456789/4513
dc.description.abstractAn X-ray structure of a CLICK chemistry-based BET PROTAC bound to BRD2(BD2) inspired synthesis of JQ1 derived heterocyclic amides. This effort led to the discovery of potent BET inhibitors displaying overall improved profiles when compared to JQ1 and birabresib. A thiadiazole derived 1q (SJ1461) displayed excellent BRD4 and BRD2 affinity and high potency in the panel of acute leukaemia and medulloblastoma cell lines. A structure of 1q co-crystalised with BRD4-BD1 revealed polar interactions with the AZ/BC loops, in particular with Asn140 and Tyr139, rationalising the observed affinity improvements. In addition, exploration of pharmacokinetic properties of this class of compounds suggest that the heterocyclic amide moiety improves drug-like features. Our study led to the discovery of potent and orally bioavailable BET inhibitor 1q (SJ1461) as a promising candidate for further development.
dc.publisherElsevier
dc.relationALSAC and R35GM142772 (to MF)
dc.relationR35GM140837 (to WCKP)
dc.relationCrystallographic data were collected at Southeast Regional Collaborative Access Team (SER-CAT) 22-ID beam- line at the Advanced Photon Source, Argonne National Laboratory.
dc.relationSER-CAT is supported by its member institutions, and equipment grants (S10_RR25528, S10_RR028976 and S10_OD027000) from the National Institutes of Health.
dc.relationThe Advanced Photon Source was supported by the U. S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38
dc.relationThe Science fund of the Republic of Serbia: program, Diaspora
dc.relationGrant no: 6463913
dc.relationinfo:eu-repo/grantAgreement/MESTD/inst-2020/200161/RS//
dc.rightsrestrictedAccess
dc.sourceEuropean Journal of Medicinal Chemistry
dc.subjectAmides
dc.subjectBET inhibitors
dc.subjectJQ1
dc.titleFrom PROTAC to inhibitor: Structure-guided discovery of potent and orally bioavailable BET inhibitors
dc.typearticle
dc.rights.licenseARR
dc.citation.volume251
dc.citation.rankaM21~
dc.identifier.wos000952151800001
dc.identifier.doi10.1016/j.ejmech.2023.115246
dc.identifier.pmid36898329
dc.identifier.scopus2-s2.0-85149446323
dc.type.versionpublishedVersion


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