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Exploration of a 14-3-3 PPI Pocket by Covalent Fragments as Stabilizers.

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Sijbesma E, Hallenbeck KK, Andrei SA, Rust RR, Adriaans JMC, Brunsveld L, Arkin MR, Ottmann C
OpenAccess logo ACS Med Chem Lett 12 976-982 (2021)
Related entries: 7b9m, 7b9r, 7b9t, 7ba3, 7ba5, 7ba6, 7ba7, 7ba8, 7baa, 7bab

Cited: 7 times
EuropePMC logo PMID: 34136078

Abstract

The systematic discovery of functional fragments binding to the composite interface of protein complexes is a first critical step for the development of orthosteric stabilizers of protein-protein interactions (PPIs). We have previously shown that disulfide trapping successfully yielded covalent stabilizers for the PPI of 14-3-3 with the estrogen receptor ERα. Here we provide an assessment of the composite PPI target pocket and the molecular characteristics of various fragments binding to a specific subpocket. Evaluating structure-activity relationships highlights the basic principles for PPI stabilization by these covalent fragments that engage a relatively large and exposed binding pocket at the protein/peptide interface with a "molecular glue" mode of action.

Reviews citing this publication (3)

  1. Molecular Glue Discovery: Current and Future Approaches. Dewey JA, Delalande C, Azizi SA, Lu V, Antonopoulos D, Babnigg G. J Med Chem 66 9278-9296 (2023)
  2. Protein-protein interactions: developing small-molecule inhibitors/stabilizers through covalent strategies. Lucero B, Francisco KR, Liu LJ, Caffrey CR, Ballatore C. Trends Pharmacol Sci 44 474-488 (2023)
  3. Contemporary biophysical approaches for studying 14-3-3 protein-protein interactions. Thurairajah B, Hudson AJ, Doveston RG. Front Mol Biosci 9 1043673 (2022)

Articles citing this publication (4)

  1. Structure-Based Optimization of Covalent, Small-Molecule Stabilizers of the 14-3-3σ/ERα Protein-Protein Interaction from Nonselective Fragments. Konstantinidou M, Visser EJ, Vandenboorn E, Chen S, Jaishankar P, Overmans M, Dutta S, Neitz RJ, Renslo AR, Ottmann C, Brunsveld L, Arkin MR. J Am Chem Soc 145 20328-20343 (2023)
  2. A synthetic peptide from Sipunculus nudus promotes bone formation via Estrogen/MAPK signal pathway based on network pharmacology. Wang P, Feng Z, Chen S, Liang Y, Hou H, Ouyang Q, Yu H, Ye H, Cai L, Qi Y, Wu K, Luo H. Front Pharmacol 14 1173110 (2023)
  3. Template-assisted covalent modification underlies activity of covalent molecular glues. Li YD, Ma MW, Hassan MM, Hunkeler M, Teng M, Puvar K, Rutter JC, Lumpkin RJ, Sandoval B, Jin CY, Schmoker AM, Ficarro SB, Cheong H, Metivier RJ, Wang MY, Xu S, Byun WS, Groendyke BJ, You I, Sigua LH, Tavares I, Zou C, Tsai JM, Park PMC, Yoon H, Majewski FC, Sperling HT, Marto JA, Qi J, Nowak RP, Donovan KA, Słabicki M, Gray NS, Fischer ES, Ebert BL. Nat Chem Biol (2024)
  4. A model-informed method to retrieve intrinsic from apparent cooperativity and project cellular target occupancy for ternary complex-forming compounds. Stein RR, Fouché M, Kearns JD, Roth HJ. RSC Chem Biol 4 512-523 (2023)


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