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@ARTICLE{Weller:638759,
      author       = {Weller, Caroline and Burnett, G. Leslie and Jiang, Lingyan
                      and Chakraborty, Sujata and Zhang, Dongyu and Vita, Nicole
                      A. and Dilly, Julien and Kim, Eejung and Maldonato, Benjamin
                      and Seamon, Kyle and Eilerts, Diane F. and Milin, Anthony
                      and Marquez, Abby and Spradlin, Jessica and Helland, Ciara
                      and Gould, Andrea and Ziv, Tamar Bar and Dinh, Phuong and
                      Steele, Shelby L. and Wang, Zhican and Mu, Yunming and
                      Chugh, Seema and Feng, Hanrong and Hennessey, Conner and
                      Wang, Junning and Roth, Jennifer and Rees, Matthew and
                      Ronan, Melissa and Wolpin, Brian M. and Hahn, William C. and
                      Holderfield, Matthew and Wang, Zhengping and Koltun, Elena
                      S. and Singh, Mallika and Gill, Adrian L. and Smith,
                      Jacqueline A. M. and Aguirre, Andrew J. and Jiang, Jingjing
                      and Knox, John E. and Wildes, David},
      title        = {{A} neomorphic protein interface catalyzes covalent
                      inhibition of {RAS} {G}12{D} aspartic acid in tumors},
      journal      = {Science / Science now},
      volume       = {389},
      number       = {6758},
      issn         = {0036-8075},
      address      = {Washington, DC},
      publisher    = {Assoc.},
      reportid     = {PUBDB-2025-04190},
      pages        = {eads0239},
      year         = {2025},
      note         = {ISSN 1095-9203 not unique: **3 hits**. Waiting for
                      fulltext},
      abstract     = {INTRODUCTIONMutant 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.},
      cin          = {EMBL-User},
      ddc          = {320},
      cid          = {I:(DE-H253)EMBL-User-20120814},
      pnm          = {6G3 - PETRA III (DESY) (POF4-6G3)},
      pid          = {G:(DE-HGF)POF4-6G3},
      experiment   = {EXP:(DE-H253)P-P13-20150101},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40705880},
      doi          = {10.1126/science.ads0239},
      url          = {https://bib-pubdb1.desy.de/record/638759},
}