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000643033 0247_ $$2doi$$a10.1038/s42004-025-01641-9
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000643033 1001_ $$00000-0003-3532-1085$$aGlaza, Przemysław$$b0
000643033 245__ $$aTargeted degradation of GSPT1 and NEK7 by a molecular glue prodrug for treatment of HCC
000643033 260__ $$a[London]$$bMacmillan Publishers Limited, part of Springer Nature$$c2025
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000643033 500__ $$aProposal P-20010353
000643033 520__ $$aTargeted Protein Degradation (TPD) technology, in the form of CRBN-modulating molecular glues, offers numerous unprecedented therapeutic benefits as evidenced by the success of approved high-value immunomodulatory imide drugs (IMiDs) such as lenalidomide and pomalidomide. Building upon these successes, we employed a small CRBN-focused library of molecular glues in a phenotypic screen against hepatocellular carcinoma (HCC) cell lines. While the original library was primarily designed to target SALL4, we identified additional CRBN substrates, including GSPT1, NEK7, and CK1α, whose degradation potently induced cell death in HCC cell lines. Subsequent lead optimization efforts yielded a compound, ABS-752, which demonstrated superior in vitro and in vivo activity through the potent degradation of GSPT1. Notably, ABS-752 does not form ternary complexes with CRBN and the neosubstrates. Further investigations revealed that ABS-752 is a prodrug activated by the monoamine oxidase, VAP-1, to an aldehyde intermediate and subsequently to the active molecule, ABT-002. VAP-1, which is overexpressed in cirrhotic liver, was identified as the primary monoamine oxidase responsible for the conversion of ABS-752. ABS-752 is currently in clinical trials for the treatment of HCC. 
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000643033 7001_ $$0P:(DE-HGF)0$$aPluta, Roman$$b1
000643033 7001_ $$0P:(DE-HGF)0$$aOdrzywół, Krzysztofa E.$$b2
000643033 7001_ $$0P:(DE-H253)PIP1097006$$aKlejnot, Marta$$b3
000643033 7001_ $$0P:(DE-HGF)0$$aWieczorek, Maria$$b4
000643033 7001_ $$0P:(DE-HGF)0$$aCottens, Sylvain$$b5
000643033 7001_ $$0P:(DE-HGF)0$$aCoppen, Donald$$b6
000643033 7001_ $$0P:(DE-HGF)0$$aDobrzański, Paweł$$b7
000643033 7001_ $$0P:(DE-HGF)0$$aDrmota, Tomas$$b8
000643033 7001_ $$0P:(DE-HGF)0$$aLis-Grześniak, Joanna$$b9
000643033 7001_ $$0P:(DE-HGF)0$$aŚnieżewska, Agata$$b10
000643033 7001_ $$0P:(DE-HGF)0$$aMajkut, Joanna$$b11
000643033 7001_ $$0P:(DE-HGF)0$$aMianowska, Martyna$$b12
000643033 7001_ $$00009-0003-8791-8331$$aRozborska, Paulina$$b13
000643033 7001_ $$0P:(DE-HGF)0$$aJarmuszkiewicz, Marta$$b14
000643033 7001_ $$0P:(DE-HGF)0$$aKaczanowska, Katarzyna$$b15
000643033 7001_ $$0P:(DE-HGF)0$$aAdamska, Aleksandra$$b16
000643033 7001_ $$0P:(DE-HGF)0$$aTakagi, Toshimitsu$$b17
000643033 7001_ $$0P:(DE-HGF)0$$aSawicka, Anna$$b18
000643033 7001_ $$00000-0002-4553-0908$$aSerwotka-Suszczak, Anna$$b19
000643033 7001_ $$0P:(DE-HGF)0$$aMakowska, Olga$$b20
000643033 7001_ $$0P:(DE-H253)PIP1102919$$aGajewska, Daria$$b21
000643033 7001_ $$0P:(DE-HGF)0$$aJurczak, Kinga$$b22
000643033 7001_ $$0P:(DE-HGF)0$$aLeszkowicz, Kinga$$b23
000643033 7001_ $$0P:(DE-HGF)0$$aMankiewicz, Michał$$b24
000643033 7001_ $$0P:(DE-H253)PIP1101132$$aPrzytulski, Kamil$$b25
000643033 7001_ $$0P:(DE-H253)PIP1093929$$aWiśniewski, Janusz$$b26
000643033 7001_ $$0P:(DE-HGF)0$$aSzlachcic, Anna$$b27
000643033 7001_ $$0P:(DE-HGF)0$$aWalczak, Michał J.$$b28$$eCorresponding author
000643033 773__ $$0PERI:(DE-600)2929562-2$$a10.1038/s42004-025-01641-9$$gVol. 8, no. 1, p. 247$$n1$$p247$$tCommunications chemistry$$v8$$x2399-3669$$y2025
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