000638759 001__ 638759
000638759 005__ 20251119161840.0
000638759 0247_ $$2doi$$a10.1126/science.ads0239
000638759 0247_ $$2ISSN$$a0036-8075
000638759 0247_ $$2ISSN$$a1095-9203
000638759 0247_ $$2ISSN$$a1947-8062
000638759 0247_ $$2altmetric$$aaltmetric:179631110
000638759 0247_ $$2pmid$$apmid:40705880
000638759 0247_ $$2openalex$$aopenalex:W4412622915
000638759 037__ $$aPUBDB-2025-04190
000638759 041__ $$aEnglish
000638759 082__ $$a320
000638759 1001_ $$00009-0000-0381-3822$$aWeller, Caroline$$b0
000638759 245__ $$aA neomorphic protein interface catalyzes covalent inhibition of RAS G12D aspartic acid in tumors
000638759 260__ $$aWashington, DC$$bAssoc.$$c2025
000638759 3367_ $$2DRIVER$$aarticle
000638759 3367_ $$2DataCite$$aOutput Types/Journal article
000638759 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1760530623_211116
000638759 3367_ $$2BibTeX$$aARTICLE
000638759 3367_ $$2ORCID$$aJOURNAL_ARTICLE
000638759 3367_ $$00$$2EndNote$$aJournal Article
000638759 500__ $$aISSN 1095-9203 not unique: **3 hits**.   Waiting for fulltext 
000638759 520__ $$aINTRODUCTIONMutant RAS is the primary oncogenic driver in RAS-addicted cancers. RAS proteins act as molecular switches that cycle between a guanosine triphosphate–bound “ON” state and a guanosine diphosphate–bound “OFF” state. Under normal circumstances, cell growth is tightly regulated by modulating the population of RAS in the ON versus the OFF state. In RAS-addicted cancers, mutations in RAS shift this balance towards the ON state, leading to increased RAS signaling and uncontrolled cell growth. Mutations in RAS are present in nearly a quarter of a million new cancer cases each year and are particularly frequent in pancreatic, colorectal, and lung cancers.RATIONALEHistorically, RAS-addicted cancers have been challenging to treat with targeted drug therapies. Mutant-selective inhibitors that covalently and irreversibly inactivate mutant RAS are advantageous because they target the mutant protein present only in cancer cells and can achieve sustained target engagement even in the context of variable tumor exposures that often result from typical inhibitor dosing schedules. Such irreversible inhibitors of KRASG12C, in which glycine is replaced with a reactive thiol-containing cysteine residue, have been approved for both lung and colorectal cancers, but no similar therapies are available for the most common RAS mutation, KRASG12D. This mutation introduces a carboxylate-containing aspartic acid residue that has low reactivity and high abundance on protein surfaces compared with cysteine, thereby posing substantial hurdles to the design of irreversible inhibitors that have sufficient potency and selectivity yet maintain the properties necessary to enable once-daily oral dosing.RESULTSTo create covalent inhibitors of KRASG12D, we used structure-based drug design to modify compounds that bind the abundant intracellular chaperone cyclophilin A (CYPA) and create a neomorphic protein-protein interface between CYPA and active RAS to covalently modify the D12 mutation located in the induced pocket at the interface. Precisely positioning reactive groups within this privileged environment enabled selective, enzyme-like rate enhancement of the covalent reaction between D12 and aziridine warheads that have low intrinsic reactivity. X-ray crystal structures and computational methods confirmed a role for the protein-protein interface in enabling selective reactivity. This approach yielded the investigational agent zoldonrasib (RMC-9805), currently undergoing clinical evaluation (NCT06040541), and the preclinical compound RMC-9945. These compounds efficiently covalently engaged RASG12D and potently suppressed oncogenic RAS signaling in RASG12D-mutant cancer cell lines in a CYPA-dependent manner. Consistent with the mechanism of action, the compounds exhibited low-potency noncovalent inhibition of RAS-driven proliferation in cell lines and patient-derived organoids with wild-type and non-G12D mutant RAS, and covalency conferred selectivity and durability of inhibition toward RASG12D. The chemical and metabolic stability was sufficient to enable once-daily oral dosing in mice, and zoldonrasib displayed marked antitumor activity in multiple preclinical models of KRASG12D-mutant pancreatic, lung, and colorectal cancers.CONCLUSIONCreation of a neomorphic protein-protein interface at RAS through chemical remodeling of the cellular chaperone CYPA selectively accelerated covalent bond formation between an inhibitor and an aspartic acid residue, enabling discovery of potent and irreversible inhibitors of the most common RAS mutation in human cancers. Zoldonrasib is an orally bioavailable, RAS(ON) G12D–selective covalent inhibitor that drives deep and durable tumor regressions in multiple preclinical models of KRASG12D cancers across indications. This strategy has the potential to greatly expand the repertoire of residues on cancer drivers or other proteins of therapeutic value that can be targeted by covalent warheads and may enable additional mechanisms of target modulation.
000638759 536__ $$0G:(DE-HGF)POF4-6G3$$a6G3 - PETRA III (DESY) (POF4-6G3)$$cPOF4-6G3$$fPOF IV$$x0
000638759 588__ $$aDataset connected to CrossRef, Journals: bib-pubdb1.desy.de
000638759 693__ $$0EXP:(DE-H253)P-P13-20150101$$1EXP:(DE-H253)PETRAIII-20150101$$6EXP:(DE-H253)P-P13-20150101$$aPETRA III$$fPETRA Beamline P13$$x0
000638759 7001_ $$00000-0003-2514-9373$$aBurnett, G. Leslie$$b1
000638759 7001_ $$00009-0006-7523-6968$$aJiang, Lingyan$$b2
000638759 7001_ $$00000-0003-0080-3180$$aChakraborty, Sujata$$b3
000638759 7001_ $$00000-0001-9125-816X$$aZhang, Dongyu$$b4
000638759 7001_ $$00000-0003-4985-6662$$aVita, Nicole A.$$b5
000638759 7001_ $$00000-0002-4006-5285$$aDilly, Julien$$b6
000638759 7001_ $$00000-0003-0381-0992$$aKim, Eejung$$b7
000638759 7001_ $$aMaldonato, Benjamin$$b8
000638759 7001_ $$00009-0005-5028-3752$$aSeamon, Kyle$$b9
000638759 7001_ $$00000-0002-8062-108X$$aEilerts, Diane F.$$b10
000638759 7001_ $$00000-0002-1923-7441$$aMilin, Anthony$$b11
000638759 7001_ $$00000-0001-5104-2823$$aMarquez, Abby$$b12
000638759 7001_ $$aSpradlin, Jessica$$b13
000638759 7001_ $$00009-0009-3408-4517$$aHelland, Ciara$$b14
000638759 7001_ $$00009-0003-5132-2544$$aGould, Andrea$$b15
000638759 7001_ $$00009-0008-1751-8507$$aZiv, Tamar Bar$$b16
000638759 7001_ $$00000-0002-0273-1603$$aDinh, Phuong$$b17
000638759 7001_ $$00000-0001-8816-4752$$aSteele, Shelby L.$$b18
000638759 7001_ $$00000-0002-9411-9349$$aWang, Zhican$$b19
000638759 7001_ $$aMu, Yunming$$b20
000638759 7001_ $$00000-0003-1486-0725$$aChugh, Seema$$b21
000638759 7001_ $$00000-0002-2133-5374$$aFeng, Hanrong$$b22
000638759 7001_ $$00000-0002-5579-1220$$aHennessey, Conner$$b23
000638759 7001_ $$aWang, Junning$$b24
000638759 7001_ $$00000-0002-5117-5586$$aRoth, Jennifer$$b25
000638759 7001_ $$00000-0002-2987-7581$$aRees, Matthew$$b26
000638759 7001_ $$00000-0003-4269-1404$$aRonan, Melissa$$b27
000638759 7001_ $$00000-0002-0455-1032$$aWolpin, Brian M.$$b28
000638759 7001_ $$00000-0003-2840-9791$$aHahn, William C.$$b29
000638759 7001_ $$00000-0001-8474-3220$$aHolderfield, Matthew$$b30
000638759 7001_ $$aWang, Zhengping$$b31
000638759 7001_ $$00009-0005-8720-9097$$aKoltun, Elena S.$$b32
000638759 7001_ $$00009-0003-0234-1589$$aSingh, Mallika$$b33
000638759 7001_ $$00009-0003-0914-4860$$aGill, Adrian L.$$b34
000638759 7001_ $$00000-0001-5028-8725$$aSmith, Jacqueline A. M.$$b35
000638759 7001_ $$00000-0002-0701-6203$$aAguirre, Andrew J.$$b36
000638759 7001_ $$00009-0004-2766-025X$$aJiang, Jingjing$$b37$$eCorresponding author
000638759 7001_ $$00009-0006-6246-5198$$aKnox, John E.$$b38$$eCorresponding author
000638759 7001_ $$00009-0009-3855-7270$$aWildes, David$$b39$$eCorresponding author
000638759 773__ $$0PERI:(DE-600)2089761-3$$a10.1126/science.ads0239$$gVol. 389, no. 6758, p. eads0239$$n6758$$peads0239$$tScience / Science now$$v389$$x0036-8075$$y2025
000638759 8564_ $$uhttps://www.science.org/doi/10.1126/science.ads0239
000638759 8564_ $$uhttps://bib-pubdb1.desy.de/record/638759/files/A%20neomorphic%20protein%20interface%20catalyzes%20covalent%20inhibition%20of%20RAS%20G12D%20aspartic%20acid%20in%20tumors.pdf$$yRestricted
000638759 8564_ $$uhttps://bib-pubdb1.desy.de/record/638759/files/A%20neomorphic%20protein%20interface%20catalyzes%20covalent%20inhibition%20of%20RAS%20G12D%20aspartic%20acid%20in%20tumors.pdf?subformat=pdfa$$xpdfa$$yRestricted
000638759 909CO $$ooai:bib-pubdb1.desy.de:638759$$pVDB
000638759 9131_ $$0G:(DE-HGF)POF4-6G3$$1G:(DE-HGF)POF4-6G0$$2G:(DE-HGF)POF4-600$$3G:(DE-HGF)POF4$$4G:(DE-HGF)POF$$aDE-HGF$$bForschungsbereich Materie$$lGroßgeräte: Materie$$vPETRA III (DESY)$$x0
000638759 9141_ $$y2025
000638759 915__ $$0StatID:(DE-HGF)0100$$2StatID$$aJCR$$bSCIENCE : 2022$$d2024-12-30
000638759 915__ $$0StatID:(DE-HGF)0200$$2StatID$$aDBCoverage$$bSCOPUS$$d2024-12-30
000638759 915__ $$0StatID:(DE-HGF)0300$$2StatID$$aDBCoverage$$bMedline$$d2024-12-30
000638759 915__ $$0StatID:(DE-HGF)0600$$2StatID$$aDBCoverage$$bEbsco Academic Search$$d2024-12-30
000638759 915__ $$0StatID:(DE-HGF)0030$$2StatID$$aPeer Review$$bASC$$d2024-12-30
000638759 915__ $$0StatID:(DE-HGF)0199$$2StatID$$aDBCoverage$$bClarivate Analytics Master Journal List$$d2024-12-30
000638759 915__ $$0StatID:(DE-HGF)1040$$2StatID$$aDBCoverage$$bZoological Record$$d2024-12-30
000638759 915__ $$0StatID:(DE-HGF)1060$$2StatID$$aDBCoverage$$bCurrent Contents - Agriculture, Biology and Environmental Sciences$$d2024-12-30
000638759 915__ $$0StatID:(DE-HGF)1150$$2StatID$$aDBCoverage$$bCurrent Contents - Physical, Chemical and Earth Sciences$$d2024-12-30
000638759 915__ $$0StatID:(DE-HGF)1050$$2StatID$$aDBCoverage$$bBIOSIS Previews$$d2024-12-30
000638759 915__ $$0StatID:(DE-HGF)0160$$2StatID$$aDBCoverage$$bEssential Science Indicators$$d2024-12-30
000638759 915__ $$0StatID:(DE-HGF)1030$$2StatID$$aDBCoverage$$bCurrent Contents - Life Sciences$$d2024-12-30
000638759 915__ $$0StatID:(DE-HGF)1200$$2StatID$$aDBCoverage$$bChemical Reactions$$d2024-12-30
000638759 915__ $$0StatID:(DE-HGF)1190$$2StatID$$aDBCoverage$$bBiological Abstracts$$d2024-12-30
000638759 915__ $$0StatID:(DE-HGF)1210$$2StatID$$aDBCoverage$$bIndex Chemicus$$d2024-12-30
000638759 915__ $$0StatID:(DE-HGF)0113$$2StatID$$aWoS$$bScience Citation Index Expanded$$d2024-12-30
000638759 915__ $$0StatID:(DE-HGF)0150$$2StatID$$aDBCoverage$$bWeb of Science Core Collection$$d2024-12-30
000638759 915__ $$0StatID:(DE-HGF)9950$$2StatID$$aIF >= 50$$bSCIENCE : 2022$$d2024-12-30
000638759 9201_ $$0I:(DE-H253)EMBL-User-20120814$$kEMBL-User$$lEMBL-User$$x0
000638759 980__ $$ajournal
000638759 980__ $$aVDB
000638759 980__ $$aI:(DE-H253)EMBL-User-20120814
000638759 980__ $$aUNRESTRICTED