8gjs
From Proteopedia
(Difference between revisions)
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8gjs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8gjs OCA], [https://pdbe.org/8gjs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8gjs RCSB], [https://www.ebi.ac.uk/pdbsum/8gjs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8gjs ProSAT]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8gjs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8gjs OCA], [https://pdbe.org/8gjs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8gjs RCSB], [https://www.ebi.ac.uk/pdbsum/8gjs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8gjs ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| - | == Function == | ||
| - | [https://www.uniprot.org/uniprot/MDM4_DANRE MDM4_DANRE] Inhibits p53- and p73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain (By similarity). | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
We report the discovery of sulanemadlin (ALRN-6924), the first cell-permeating, stabilized alpha-helical peptide to enter clinical trials. ALRN-6924 is a "stapled peptide" that mimics the N-terminal domain of the p53 tumor suppressor protein. It binds with high affinity to both MDM2 and MDMX (also known as MDM4), the endogenous inhibitors of p53, to activate p53 signaling in cells having a non-mutant, or wild-type TP53 genotype (TP53-WT). Iterative structure-activity optimization endowed ALRN-6924 with favorable cell permeability, solubility, and pharmacokinetic and safety profiles. Intracellular proteolysis of ALRN-6924 forms a long-acting active metabolite with potent MDM2 and MDMX binding affinity and slow dissociation kinetics. At high doses, ALRN-6924 exhibits on-mechanism anticancer activity in TP53-WT tumor models. At lower doses, ALRN-6924 transiently arrests the cell cycle in healthy tissues to protect them from chemotherapy without protecting the TP53-mutant cancer cells. These results support the continued clinical evaluation of ALRN-6924 as an anticancer and chemoprotection agent. | We report the discovery of sulanemadlin (ALRN-6924), the first cell-permeating, stabilized alpha-helical peptide to enter clinical trials. ALRN-6924 is a "stapled peptide" that mimics the N-terminal domain of the p53 tumor suppressor protein. It binds with high affinity to both MDM2 and MDMX (also known as MDM4), the endogenous inhibitors of p53, to activate p53 signaling in cells having a non-mutant, or wild-type TP53 genotype (TP53-WT). Iterative structure-activity optimization endowed ALRN-6924 with favorable cell permeability, solubility, and pharmacokinetic and safety profiles. Intracellular proteolysis of ALRN-6924 forms a long-acting active metabolite with potent MDM2 and MDMX binding affinity and slow dissociation kinetics. At high doses, ALRN-6924 exhibits on-mechanism anticancer activity in TP53-WT tumor models. At lower doses, ALRN-6924 transiently arrests the cell cycle in healthy tissues to protect them from chemotherapy without protecting the TP53-mutant cancer cells. These results support the continued clinical evaluation of ALRN-6924 as an anticancer and chemoprotection agent. | ||
| - | Discovery of Sulanemadlin (ALRN-6924), the First Cell-Permeating, Stabilized alpha-Helical Peptide in Clinical Development.,Guerlavais V, Sawyer TK, Carvajal L, Chang YS, Graves B, Ren JG, Sutton D, Olson KA, Packman K, Darlak K, Elkin C, Feyfant E, Kesavan K, Gangurde P, Vassilev LT, Nash HM, Vukovic V, Aivado M, Annis DA J Med Chem. 2023 Jul | + | Discovery of Sulanemadlin (ALRN-6924), the First Cell-Permeating, Stabilized alpha-Helical Peptide in Clinical Development.,Guerlavais V, Sawyer TK, Carvajal L, Chang YS, Graves B, Ren JG, Sutton D, Olson KA, Packman K, Darlak K, Elkin C, Feyfant E, Kesavan K, Gangurde P, Vassilev LT, Nash HM, Vukovic V, Aivado M, Annis DA J Med Chem. 2023 Jul 27;66(14):9401-9417. doi: 10.1021/acs.jmedchem.3c00623. Epub , 2023 Jul 13. PMID:37439511<ref>PMID:37439511</ref> |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
Current revision
Stapled Peptide ALRN-6924 Bound to MDMX
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