Review
Cell Biology
Alyssa M. Klein, Rafaela Muniz de Queiroz, Divya Venkatesh, Carol Prives
Summary: MDM2 and MDMX, well-known as proteins that restrain the p53 tumor suppressor protein, have diverse functions in cells and are regulated at multiple levels including transcription and protein modification. Both proteins may contribute to oncogenic transformation while also potentially playing a tumor suppressive role in certain contexts. Understanding how various small molecules affecting MDM2 and MDMX may impact their p53-independent activities is crucial due to their therapeutic potential.
GENES & DEVELOPMENT
(2021)
Article
Biochemistry & Molecular Biology
Dongjuan Si, Huijuan Luo, Xiaomeng Zhang, Kundi Yang, Hongmei Wen, Wei Li, Jian Liu
Summary: Inhibition of p53-MDM2 interactions is a promising strategy for cancer treatment. The unsaturated pyrrolidone compound 4h showed good binding affinity with MDM2 and demonstrated excellent antitumor activity by inducing cell cycle arrest and apoptosis. This compound has potential as a novel antitumor agent.
BIOORGANIC CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Yali Wang, Bo Ji, Zhongshui Cheng, Lianghui Zhang, Yingying Cheng, Yingying Li, Jin Ren, Wenbo Liu, Yuanyuan Ma
Summary: A series of novel indolone derivatives were synthesized and evaluated for their binding affinities toward MDM2 and MDMX. Compound A13 showed the most potent affinity and exhibited strong inhibitory effects on multiple cancer cell lines.
Review
Oncology
Murali Munisamy, Nayonika Mukherjee, Levin Thomas, Amy Trinh Pham, Arash Shakeri, Yusheng Zhao, Jill Kolesar, Praveen P. N. Rao, Vivek M. Rangnekar, Mahadev Rao
Summary: Ubiquitination is crucial in regulating p53 stability and function in cancer, particularly through the p53-MDM2-MDMX pathway. Targeting the ubiquitination pathway shows promise as a strategy for precision therapy in cancer treatment.
AMERICAN JOURNAL OF CANCER RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Viktoria K. Ilic, Olga Egorova, Ernest Tsang, Milena Gatto, Yi Wen, Yong Zhao, Yi Sheng
Summary: The proto-oncogene MDM2 is frequently amplified in many human cancers and its overexpression is associated with poor prognosis. MDM2 shows oncogenic activity by negatively regulating tumor suppressor p53 and proteins involved in DNA repair, cell cycle control, and apoptosis pathways. Inhibition of MDM2 activity has been pursued as an attractive direction for anti-cancer therapeutics. This study identified a biflavonoid compound Hinokiflavone as a promising candidate compound targeting MDM2. Hinokiflavone was shown to bind the MDM2-MDMX RING domain and inhibit MDM2-mediated ubiquitination in vitro. Hinokiflavone treatment downregulated MDM2 and MDMX and induced apoptosis in various cancer cell lines. Hinokiflavone demonstrated tumor-suppressive activity that is both p53-dependent and -independent.
Article
Chemistry, Medicinal
Hui-juan Luo, Dong-juan Si, Xin-jie Sun, Meng-yun Wang, Yao-bin Yang, Bo Wang, Hong-mei Wen, Wei Li, Jian Liu
Summary: The overexpression of MDM2 and MDMX negatively regulates the function of p53 protein. Disruption of the p53-MDM2/MDMX interaction is a potential strategy for cancer therapy. Through molecular dynamics simulations, alanine scanning, and MM-GBSA calculations, the binding modes of MDM2 and MDMX with their inhibitors are elucidated, and several hot-spot residues are identified. Based on the interaction with hot-spot residues, derivatives with 1,3-diketone and alpha-aminoketone scaffolds are designed and synthesized. Among these compounds, C16 shows the highest binding affinities with MDM2 and MDMX, and exhibits antiproliferative activities, cell migration and invasion inhibition, reactivation of p53 function, cell cycle arrest, and induction of cellular apoptosis in cancer cells.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Medicine, Research & Experimental
Si Chen, Xiang Li, Yinghua Li, Xing Yuan, Chenchen Geng, Songyan Gao, Jinyang Li, Bohan Ma, Zhe Wang, Wuyuan Lu, Hong-Gang Hu
Summary: A stapled peptide-based proteolysis-targeting chimera (SP-PROTAC) was developed, which improved cellular uptake and proteolytic stability while promoting target protein degradation. The optimized SP-PROTAC showed improved binding affinity, helical content, and pharmacokinetic profile compared to its linear counterpart. It effectively killed cancer cells and inhibited tumor progression by promoting the atypical degradation of MDM2 and MDMX and activating p53.
Article
Chemistry, Medicinal
Daniil R. Bazanov, Nikolay Pervushin, Egor Savin, Michael D. Tsymliakov, Anita Maksutova, Sergey E. Sosonyuk, Gelina S. Kopeina, Natalia A. Lozinskaya
Summary: Novel hydrophilic cis-2,4,5-tris(alkoxyphenyl)imidazolines were synthesized and their influence on protein-protein interaction compared to unsubstituted alkoxy-compounds was studied. The derivatives were found to inhibit MDM2/MDMX-p53 interaction, promote p53 stabilization and induce p21 expression in concentrations as low as 500 nM.
MEDICINAL CHEMISTRY RESEARCH
(2021)
Article
Chemistry, Medicinal
Shuai Wang, Fen-Er Chen
Summary: Inhibition of the MDM2-p53 protein-protein interaction using small-molecule inhibitors is a promising strategy for cancer therapy. Many highly potent and selective small-molecule MDM2 inhibitors have been discovered and are currently undergoing different clinical trials. This review provides an overview of the function of MDM2 and the identification, optimization, preclinical, and clinical studies of clinical-stage MDM2 inhibitors. It also discusses challenges, potential toxicity, and future perspectives, which will guide the design of new small-molecule MDM2 inhibitors.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Hongjin Li, Xiangyan Chen, Minghao Wu, Panpan Song, Xia Zhao
Summary: In recent years, inhibiting the interactions of p53 with MDM2 and MDMX has been recognized as a promising approach for tumor therapy. However, peptide inhibitors face challenges of poor proteolytical stability and low intracellular delivery efficiency. In this study, a bicyclic stapled peptide named p53-16 was designed and synthesized, which showed improved stability and binding affinity for MDM2 and MDMX. Moreover, p53-16 could penetrate cell membranes and selectively inhibit the activity of tumor cells in vitro.
CHINESE CHEMICAL LETTERS
(2022)
Article
Chemistry, Medicinal
Aoze Su, Yuko Tabata, Kiyono Aoki, Akane Sada, Rieko Ohki, Satoru Nagatoishi, Kouhei Tsumoto, Siyuan Wang, Yuko Otani, Tomohiko Ohwada
Summary: This research focused on optimizing the structure of stable helical trimers of bicyclic beta-amino acids for inhibiting the p53-MDM2/MDMX interaction. Experimental assays confirmed that the modified peptides can bind to MDM2 and act as membrane-permeable antagonists, rescuing p53 function in human osteosarcoma cells.
CHEMICAL & PHARMACEUTICAL BULLETIN
(2021)
Article
Pharmacology & Pharmacy
Xiang Li, Neelakshi Gohain, Si Chen, Yinghua Li, Xiaoyuan Zhao, Bo Li, William D. Tolbert, Wangxiao He, Marzena Pazgier, Honggang Hu, Wuyuan Lu
Summary: The research identified a potent dual-specificity peptide antagonist PMI-M3 of MDM2 and MDMX through systematic mutational analysis and additivity-based molecular design, with ultrahigh affinity and significant antitumor activities both in vitro and in vivo. The peptide inhibitor PMI-M3, occupying the P53-binding pocket of MDM2/MDMX, showed enhanced binding affinity compared to PMI, making it a powerful lead compound for anticancer drug development and aiding molecular design of other P53 activators for cancer therapy.
ACTA PHARMACEUTICA SINICA B
(2021)
Article
Chemistry, Medicinal
Gianni Chessari, Ian R. Hardcastle, Jong Sook Ahn, Burcu Anil, Elizabeth Anscombe, Ruth H. Bawn, Luke D. Bevan, Timothy J. Blackburn, Ildiko Buck, Celine Cano, Benoit Carbain, Juan Castro, Ben Cons, Sarah J. Cully, Jane A. Endicott, Lynsey Fazal, Bernard T. Golding, Roger J. Griffin, Karen Haggerty, Suzannah J. Harnor, Keisha Hearn, Stephen Hobson, Rhian S. Holvey, Steven Howard, Claire E. Jennings, Christopher N. Johnson, John Lunec, Duncan C. Miller, David R. Newell, Martin E. M. Noble, Judith Reeks, Charlotte H. Revill, Christiane Riedinger, Jeffrey D. St Denis, Emiliano Tamanini, Huw Thomas, Neil T. Thompson, Mladen Vinkovic, Stephen R. Wedge, Pamela A. Williams, Nicola E. Wilsher, Bian Zhang, Yan Zhao
Summary: In this study, novel isoindolinone-based MDM2 inhibitors were designed with rational structure guidance and showed potent inhibition of MDM2-p53 interaction, leading to cytostasis in an osteosarcoma xenograft model. These findings highlight the potential of targeting MDM2 in cancer therapy.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Oncology
Atif Zafar, Wei Wang, Gang Liu, Wa Xian, Frank McKeon, Jia Zhou, Ruiwen Zhang
Summary: Neuroblastoma poses a significant challenge in pediatric oncology, with p53 protein playing a key protective role against genome instability. Overexpression of MDM2 in neuroblastoma can lead to p53 inhibition, drug resistance, and other non-canonical p53 functions. Research is focused on restoring p53 function by targeting the p53-MDM2 axis for potential therapeutic strategies.
Article
Oncology
Renier C. Heijkants, Amina F. A. S. Teunisse, Danielle de Jong, Kseniya Glinkina, Hailiang Mei, Szymon M. Kielbasa, Karoly Szuhai, Aart G. Jochemsen
Summary: The tumor suppressor protein p53 is frequently repressed in cancer cells by high levels of MDMX and/or MDM2. This study suggests that the oncogenic functions of MDMX can be partially explained by its regulation of FOXO transcription factors, independent of p53.
Article
Biochemistry & Molecular Biology
Paolo Dognini, Patrick M. Killoran, George S. Hanson, Lewis Halsall, Talhat Chaudhry, Zasharatul Islam, Francesca Giuntini, Christopher R. Coxon
Summary: This study investigated the effects of base and solvent on the reactivity and product selectivity of hexafluorobenzene in a model reaction. New conditions were identified which selectively afford higher order substitution products such as 1,2,4,5-tetrasubstitution, making hexafluorobenzene a promising scaffold for future branched or multicyclic peptide systems. Additionally, these new conditions provide an improved rapid (<1 minute) and selective peptide disulfide stapling and cyclisation approach under peptide-compatible conditions.
Article
Chemistry, Medicinal
Yamir Islam, Parinaz Ehtezazi, Andrew Cashmore, Elena Marinsalda, Andrew G. Leach, Christopher R. Coxon, Amos A. Fatokun, Darren W. Sexton, Iftikhar Khan, Georgios Zouganelis, James Downing, Stefano Pluchino, Muttuswamy Sivakumaran, Meritxell Teixido, Touraj Ehtezazi
Summary: The study investigated whether including MMP-9-sensitive sequences in brain-targeting nanoparticles could enhance BBB penetration during elevated MMP-9 levels, leading to increased transport across the BBB model when MMP-9 levels were elevated and the brain-targeting ligand was responsive to MMP-9.
JOURNAL OF PHARMACEUTICAL SCIENCES
(2021)
Review
Pharmacology & Pharmacy
Vera D'Aloisio, Paolo Dognini, Gillian A. Hutcheon, Christopher R. Coxon
Summary: By 2020, over 100 approved peptides for therapeutic or diagnostic purposes had been developed, but the lack of a comprehensive free database poses a challenge for designing future peptide drug candidates. Unlike small-molecule drugs, there is no general set of guidelines for designing successful peptide-based drugs currently available.
DRUG DISCOVERY TODAY
(2021)
Review
Biochemistry & Molecular Biology
Paolo Dognini, Christopher R. Coxon, Wendel A. Alves, Francesca Giuntini
Summary: The covalent and noncovalent association of self-assembling peptides and tetrapyrroles can generate systems that mimic Nature's functional supramolecular structures, enhancing the photochemical properties of embedded chromophores and enabling various applications.
Article
Chemistry, Medicinal
Tian-jiao Zhou, Jun-feng Liu, Ping Wang, An-na Hu, Lin-lin Chen, Jun-feng Zan
Summary: The study employed network pharmacology to investigate the therapeutic effects of Yiqi Sanjie formula on lung cancer. Through regulating multiple signaling pathways, it was found that the formula may have potential therapeutic targets against lung cancer. The combinational network pharmacology analysis indicated that Yiqi Sanjie formula might alleviate lung neoplasm symptoms through multiple targets in a synergetic way.
NATURAL PRODUCT COMMUNICATIONS
(2021)
Article
Chemistry, Medicinal
Gianni Chessari, Ian R. Hardcastle, Jong Sook Ahn, Burcu Anil, Elizabeth Anscombe, Ruth H. Bawn, Luke D. Bevan, Timothy J. Blackburn, Ildiko Buck, Celine Cano, Benoit Carbain, Juan Castro, Ben Cons, Sarah J. Cully, Jane A. Endicott, Lynsey Fazal, Bernard T. Golding, Roger J. Griffin, Karen Haggerty, Suzannah J. Harnor, Keisha Hearn, Stephen Hobson, Rhian S. Holvey, Steven Howard, Claire E. Jennings, Christopher N. Johnson, John Lunec, Duncan C. Miller, David R. Newell, Martin E. M. Noble, Judith Reeks, Charlotte H. Revill, Christiane Riedinger, Jeffrey D. St Denis, Emiliano Tamanini, Huw Thomas, Neil T. Thompson, Mladen Vinkovic, Stephen R. Wedge, Pamela A. Williams, Nicola E. Wilsher, Bian Zhang, Yan Zhao
Summary: In this study, novel isoindolinone-based MDM2 inhibitors were designed with rational structure guidance and showed potent inhibition of MDM2-p53 interaction, leading to cytostasis in an osteosarcoma xenograft model. These findings highlight the potential of targeting MDM2 in cancer therapy.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Alessandro Streuli, Christopher R. Coxon, Christian Steuer
Summary: The analysis of counter ions in small molecules and synthetic peptides is a challenging task in academia and industry, requiring simple and generic quantification methods. A quantitative mixed mode high performance liquid chromatography method coupled to evaporative light scattering detection was used to successfully quantify 14 counter ions, validating its applicability.
JOURNAL OF PHARMACEUTICAL SCIENCES
(2021)
Article
Chemistry, Organic
Christopher G. Thomson, Colin Banks, Mark Allen, Graeme Barker, Christopher R. Coxon, Ai-Lan Lee, Filipe Vilela
Summary: Recent advancements in in-line extraction and purification technology have made complex multistep synthesis in continuous flow reactor systems possible. The integration of a commercial automated flash chromatography system with a flow reactor enables continuous synthesis and isolation of products with high purity.
JOURNAL OF ORGANIC CHEMISTRY
(2021)
Review
Chemistry, Multidisciplinary
William D. G. Brittain, Christopher R. Coxon
Summary: Perfluoroaromatic reagents are diverse and exciting tools for modifying peptides and proteins due to their nucleophilic substitution chemistry, high electron deficiency, and tunable reactivity towards specific nucleophiles. They can be used as protecting groups or activating groups in peptide synthesis, as well as for chemoselective tagging, stapling, bioconjugation, and tuning of drug-like properties. Potential future applications of these reagents in biological chemistry will also be explored in this review.
CHEMISTRY-A EUROPEAN JOURNAL
(2022)
Article
Chemistry, Multidisciplinary
Patrick M. Killoran, George S. M. Hanson, Sanne J. M. Verhoork, Madeleine Smith, Davide Del Gobbo, Lu-Yun Lian, Christopher R. Coxon
Summary: A method using 4-fluorophenylalanine as a reporter group for F-19 NMR was developed to measure the conformational status of peptidylprolyl bonds in peptide models. This method was applied to study the prolyl bond status in pentapeptide models of the intrinsically disordered region of alpha-synuclein. It was demonstrated that F-19 NMR is a valuable tool for studying proline isomerism under different conditions.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)
Article
Chemistry, Multidisciplinary
Paolo Dognini, Talhat Chaudhry, Giulia Scagnetti, Michele Assante, George S. M. Hanson, Kehinde Ross, Francesca Giuntini, Christopher R. Coxon
Summary: This study presents a method for peptide cyclisation using polyfluorinated aromatic reagents and thiolates through nucleophilic aromatic substitution (SNAr). The resulting peptide scaffolds offer new possibilities for 3D peptide architectures. The method demonstrates chemoselectivity and wide applicability, allowing for stapling and multicyclisation of non-protected peptides. Additionally, a porphyrin-templated stapled peptide with skin cell penetrating ability and intrinsic fluorescence was developed.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)
Article
Biochemistry & Molecular Biology
Vera D'Aloisio, Adam Schofield, David A. Kendall, Gillian A. Hutcheon, Christopher R. Coxon
Summary: Evaluation of peptide drug candidates stability in biological fluids is crucial in lead optimisation phase. This study presents an optimised and validated method for evaluating the stability of a calcitonin gene-related peptide antagonist peptide (P006) in blood serum. The method was optimised using Plackett-Burman design and Taguchi design, and compliance to International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines was validated. The optimised method allowed successful separation and identification of major metabolites of P006, providing a robust early-stage platform for screening peptide stability.
JOURNAL OF PEPTIDE SCIENCE
(2023)
Article
Chemistry, Organic
O. Stephen Ojo, Hannah J. Steel, Haralampos N. Miras
Summary: This study describes the 1,4-reduction of β- and γ-substituted butenolides using 5 mol% of NiCl2 & BULL;6H(2)O and NaBH4 in MeOH, providing a rapid access to cis-β,γ-disubstituted γ-butyrolactones. The reaction selectively produces cis-products with good to excellent yields. The influence of steric hindrance and angle strain on the diastereoselectivity of conjugate reductions using in situ generated nickel-hydride is showcased.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2023)
Article
Chemistry, Organic
O. Stephen Ojo, David L. Hughes, Christopher J. Richards
Summary: The parent Josiphos ligand showed high enantioselectivity (95-99%) and good yields (60-97%) in the copper-catalysed asymmetric conjugate reduction of beta-aryl alpha,beta-unsaturated lactones and lactams with PMHS. These substrates were obtained from stereospecific copper-catalysed addition of arylboronic acids to alkynoates, followed by deprotection and cyclisation. The acyclic lactam precursors also underwent reduction with good enantioselectivity (83-85%) and yields (79-95%). Application of this asymmetric reduction methodology included the synthesis of the natural product lucidulactone A.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2023)
Review
Chemistry, Multidisciplinary
William D. G. Brittain, Christopher R. Coxon
Summary: Perfluoroaromatic reagents have a diverse range of applications in modifying peptides and proteins, such as serving as protecting or activating groups in peptide synthesis, chemoselective tagging, stapling, bioconjugation, and tuning drug-like properties. There is potential for further future applications in biological chemistry.
CHEMISTRY-A EUROPEAN JOURNAL
(2022)
