ArticleACS chemical biology2016
Harnessing Fluorine-Sulfur Contacts and Multipolar Interactions for the Design of p53 Mutant Y220C Rescue Drugs.
Article in ACS chemical biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers, 1 of them a synthesis that pooled it.
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Who cites it
41 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Targeting p53 pathways: mechanisms, structures, and advances in therapy.Signal transduction and targeted therapy · 2023Pooled it
- Facile Cobalt-supported Zeolite 4 A as ecofriendly catalyst to prepare 2-Furyl- hydrazine-1-carbothioamides and 1,2,4 Triazole-3-thiones with anticancer investigation.Scientific reports · 2026Article
- Coordination Geometry and Structure-Property Relationships in Alkaline-Earth β‑Diketonate Complexes with 2‑Methylimidazole.ACS omega · 2026Article
- Targeting the p53 cancer mutants Y220C, Y220N, and Y220S with the small-molecule stabilizer rezatapopt.Cell death & disease · 2026Article
- Hidden Interactions: Quantum Perspectives in Drug Design.Methods in molecular biology (Clifton, N.J.) · 2026Review
- intDesc-AbMut: A Tool for Describing and Understanding How Antibody Mutations Impact Their Environmental Interactions.Computational and structural biotechnology journal · 2026Article
- TowardsbioRxiv : the preprint server for biology · 2025Article
- Identification of chrysin derivatives anticancer potential in MCF7 cells: biological insights and in silico evaluation.Future medicinal chemistry · 2025Article
- Highlights on U.S. FDA-approved halogen-containing drugs in 2024.European journal of medicinal chemistry · 2025Review
- Discovery of Rezatapopt (PC14586), a First-in-Class, Small-Molecule Reactivator of p53 Y220C Mutant in Development.ACS medicinal chemistry letters · 2025Article
- SDrug design, development and therapy · 2025Article
- Covalent Fragments Acting as Tyrosine Mimics for Mutant p53-Y220C Rescue by Nucleophilic Aromatic Substitution.ACS pharmacology & translational science · 2024Article
- 20S proteasome enhancers prevent cytotoxic tubulin polymerization-promoting protein induced α-synuclein aggregation.iScience · 2024Article
- A new wave of innovations within the DNA damage response.Signal transduction and targeted therapy · 2023Review
- Principles and Applications of CFJournal of medicinal chemistry · 2023Review
- Development and Characterization of Novel Selective, Non-Basic Dopamine DMolecules (Basel, Switzerland) · 2023Article
- Design, Synthesis and Antitumor Activity of 1International journal of molecular sciences · 2023Article
- Synthesis of Amino Acids Bearing Halodifluoromethyl Moieties and Their Application to p53-Derived Peptides Binding to Mdm2/Mdm4.Drug design, development and therapy · 2023Article
- Transition of amyloid/mutant p53 from tumor suppressor to an oncogene and therapeutic approaches to ameliorate metastasis and cancer stemness.Cancer cell international · 2022Review
- Revisiting a challenging p53 binding site: a diversity-optimized HEFLib reveals diverse binding modes in T-p53C-Y220C.RSC medicinal chemistry · 2022Article
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Authors and funding
8 authors.
Funding
Abstract
Many oncogenic mutants of the tumor suppressor p53 are conformationally unstable, including the frequently occurring Y220C mutant. We have previously developed several small-molecule stabilizers of this mutant. One of these molecules, PhiKan083, 1-(9-ethyl-9H-carbazole-3-yl)-N-methylmethanamine, binds to a mutation-induced surface crevice with a KD = 150 μM, thereby increasing the melting temperature of the protein and slowing its rate of aggregation. Incorporation of fluorine atoms into small molecule ligands can substantially improve binding affinity to their protein targets. We have, therefore, harnessed fluorine-protein interactions to improve the affinity of this ligand. Step-wise introduction of fluorines at the carbazole ethyl anchor, which is deeply buried within the binding site in the Y220C-PhiKan083 complex, led to a 5-fold increase in affinity for a 2,2,2-trifluoroethyl anchor (ligand efficiency of 0.3 kcal mol(-1) atom(-1)). High-resolution crystal structures of the Y220C-ligand complexes combined with quantum chemical calculations revealed favorable interactions of the fluorines with protein backbone carbonyl groups (Leu145 and Trp146) and the sulfur of Cys220 at the mutation site. Affinity gains were, however, only achieved upon trifluorination, despite favorable interactions of the mono- and difluorinated anchors with the binding pocket, indicating a trade-off between energetically favorable protein-fluorine interactions and increased desolvation penalties. Taken together, the optimized carbazole scaffold provides a promising starting point for the development of high-affinity ligands to reactivate the tumor suppressor function of the p53 mutant Y220C in cancer cells.
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