Revisiting a challenging p53 binding site: a diversity-optimized HEFLib reveals diverse binding modes in T-p53C-Y220C

Stahlecker, Jason; Klett, Theresa; Schwer, Martin; Jaag, Simon; Dammann, Marcel; Ernst, Larissa N; Braun, Michael B.; Zimmermann, Markus O.; Krämer, M.; Lämmerhofer, Michael; Stehle, Thilo; Coles, Murray; Boeckler, Frank M.

doi:10.1039/d2md00246a

Cited by 8 publications

(5 citation statements)

References 62 publications

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“…(4) Dammann et al developed a halogen-enriched fragment library (HEFLib) to evaluate the σ-hole of halogens (Cl, Br, and I) targeting specific interactions with electron-rich regions of proteins. DYRK1a and a mutant form of P53 (Y220C) were used as example systems. , …”

Section: Resultsmentioning

confidence: 99%

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Fragment-to-Lead Medicinal Chemistry Publications in 2022

Woodhead,

Erlanson,

de Esch

et al. 2024

J. Med. Chem.

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This Perspective is the eighth in an annual series that summarizes successful fragment-to-lead (F2L) case studies published each year. A tabulated summary of relevant articles published in 2022 is provided, and features such as target class, screening methods, and ligand efficiency are discussed both for the 2022 examples and for the combined examples over the years 2015−2022. In addition, trends and new developments in the field are summarized. In 2022, 18 publications described successful fragment-to-lead studies, including the development of three clinical compounds (MTRX1719, MK-8189, and BI-823911). ■ SIGNIFICANCEFragment-based methodologies have become firmly established within the drug discovery community, and with the recent FDA approval of capivasertib, there are now seven fragment-derived drugs approved for clinical use. This Perspective provides case studies of successful fragment-tolead examples for 2022 and discusses various trends, including target classes, screening methods, and physicochemical properties, compared with previous years.

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Section: Resultsmentioning

confidence: 99%

“…DYRK1a and a mutant form of P53 (Y220C) were used as example systems. 71,72 Computational Methodology. Computational methods have become a fundamental part of FBDD in both hit identification and hit follow-up.…”

Section: Resultsmentioning

confidence: 99%

Fragment-to-Lead Medicinal Chemistry Publications in 2022

Woodhead,

Erlanson,

de Esch

et al. 2024

J. Med. Chem.

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“…To demonstrate the use of CF 2 X in targeting binding sites, we have synthesized a series of fragments bearing R−NHCO–CF 2 X with diversified scaffolds (R = organic scaffold; X = Cl, Br, I) as an addition to our HEFLibs concept. ,,− The advantage of this fragment-based strategy is its focus on only a few relevant key interactions. Using STD NMR and ITC as primary and secondary biophysical screening techniques, respectively, we applied this small library of CF 2 X-fragments to the c-Jun N-terminal kinases 1 and 3 (JNK1 and JNK3). , Here we focused on halogenated acetamides because their synthesis is much simpler, faster, and cheaper, which facilitates the rapid establishment of a fragment library enriched in CF 2 X acetamides.…”

Section: Resultsmentioning

confidence: 99%

Principles and Applications of CF₂X Moieties as Unconventional Halogen Bond Donors in Medicinal Chemistry, Chemical Biology, and Drug Discovery

Vaas,

Zimmermann,

Schollmeyer

et al. 2023

J. Med. Chem.

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As an orthogonal principle to the established (hetero)aryl halides, we herein highlight the usefulness of CF 2 X (X = Cl, Br, or I) moieties. Using tool compounds bearing CF 2 X moieties, we study their chemical/metabolic stability and their logP/solubility, as well as the role of XB in their small molecular crystal structures. Employing QM techniques, we analyze the observed interactions, provide insights into the conformational flexibilities and preferences in the potential interaction space. For their application in molecular design, we characterize their XB donor capacities and its interaction strength dependent on geometric parameters. Implementation of CF 2 X acetamides into our HEFLibs and biophysical evaluation (STD-NMR/ITC), followed by X-ray analysis, reveals a highly interesting binding mode for fragment 23 in JNK3, featuring an XB of CF 2 Br toward the P-loop, as well as chalcogen bonds. We suggest that underexplored chemical space combined with unconventional binding modes provides excellent opportunities for patentable chemotypes for therapeutic intervention. ■ SIGNIFICANCEStarting from asciminib, we thoroughly characterize the great potential of CF 2 X moieties as strong halogen bond donors with a multitude of experimental and computational methods. While traditionally halogens in drug-like molecules are only attached to (hetero)aryl systems, these new moieties facilitate the escape from planarity into the third dimension. Hence, they provide completely new opportunities to harness the highly directional XB interactions in drug design and discovery.

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“…34,35 Rescuing p53 mutations and targeting the p53 regulatory network has been a focal point of our research. 24,[36][37][38][39][40][41][42][43] The proteins Mdm2 and Mdm4 are negative regulators of p53, and their interaction is a common model system for evaluating inhibition of protein-protein interactions (PPIs). 44 Both proteins bind to the same sequence in the intrinsically disordered N-terminus of p53 with their structurally very similar N-terminal domains.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Amino Acids Bearing Halodifluoromethyl Moieties and Their Application to p53-Derived Peptides Binding to Mdm2/Mdm4

Vaas¹,

Zimmermann²,

Klett³

et al. 2023

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Therapeutic peptides are a significant class of drugs in the treatment of a wide range of diseases. To enhance their properties, such as stability or binding affinity, they are usually chemically modified. This includes, among other techniques, cyclization of the peptide chain by bridging, modifications to the backbone, and incorporation of unnatural amino acids. One approach previously established, is the use of halogenated aromatic amino acids. In principle, they are thereby enabled to form halogen bonds (XB). In this study, we focus on the -R-CF 2 X moiety (R = O, NHCO; X = Cl, Br) as an uncommon halogen bond donor. These groups enable more spatial variability in protein-protein interactions. The chosen approach via Fmoc-protected building blocks allows for the incorporation of these modified amino acids in peptides using solid-phase peptide synthesis. Results and Discussion: Using a competitive fluorescence polarization assay to monitor binding to Mdm4, we demonstrate that a p53-derived peptide with Lys24Nle(εNHCOCF 2 X) exhibits an improved inhibition constant K i compared to the unmodified peptide. Decreasing K i values observed with the increasing XB capacity of the halogen atoms (F ≪ Cl < Br) indicates the formation of a halogen bond. By reducing the side chain length of Nle(εNHCOCF 2 X) to Abu(γNHCOCF 2 X) as control experiments and through quantum mechanical calculations, we suggest that the observed affinity enhancement is related to halogen bond-induced intramolecular stabilization of the α-helical binding mode of the peptide or a direct interaction with His54 in human Mdm4.

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Revisiting a challenging p53 binding site: a diversity-optimized HEFLib reveals diverse binding modes in T-p53C-Y220C

Abstract: Fragment screening of the challenging drug target T-p53-Y220C with our diversity optimized HEFLib leads to diverse reversible and covalent binding modes.

Cited by 8 publications

References 62 publications

Fragment-to-Lead Medicinal Chemistry Publications in 2022

Fragment-to-Lead Medicinal Chemistry Publications in 2022

Principles and Applications of CF₂X Moieties as Unconventional Halogen Bond Donors in Medicinal Chemistry, Chemical Biology, and Drug Discovery

Synthesis of Amino Acids Bearing Halodifluoromethyl Moieties and Their Application to p53-Derived Peptides Binding to Mdm2/Mdm4

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Revisiting a challenging p53 binding site: a diversity-optimized HEFLib reveals diverse binding modes in T-p53C-Y220C

Abstract: Fragment screening of the challenging drug target T-p53-Y220C with our diversity optimized HEFLib leads to diverse reversible and covalent binding modes.

Cited by 8 publications

References 62 publications

Fragment-to-Lead Medicinal Chemistry Publications in 2022

Fragment-to-Lead Medicinal Chemistry Publications in 2022

Principles and Applications of CF2X Moieties as Unconventional Halogen Bond Donors in Medicinal Chemistry, Chemical Biology, and Drug Discovery

Synthesis of Amino Acids Bearing Halodifluoromethyl Moieties and Their Application to p53-Derived Peptides Binding to Mdm2/Mdm4

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Product

Resources

About

Principles and Applications of CF₂X Moieties as Unconventional Halogen Bond Donors in Medicinal Chemistry, Chemical Biology, and Drug Discovery