Review
Chemistry, Medicinal
Chahat, Rohit Bhatia, Bhupinder Kumar
Summary: Cancer is a dangerous disease and p53 is a well-researched tumor suppressor protein that plays a critical role in maintaining genetic stability and controlling various cellular processes. Abnormalities in p53 contribute to genetic instability and carcinogenesis. Enhancing p53 activity in cancer cells is a promising anticancer strategy. This article discusses the current advancements in anti-tumor activities targeting p53-MDM2 and emphasizes the structure-activity relationship characteristics (SAR).
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
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
Biochemistry & Molecular Biology
Prosper Obed Chukwuemeka, Haruna Isiyaku Umar, Opeyemi Iwaloye, Oluwaseyi Matthew Oretade, Christopher Busayo Olowosoke, Michael Omoniyi Elabiyi, Festus Omotere Igbe, Oyeyemi Janet Oretade, Joy Oseme Eigbe, Funmilayo Janet Adeojo
Summary: Disrupting p53-MDM2 interactions through small molecule ligands is a promising approach for cancer treatment. By using pharmacophore-based screening and molecular docking, potential ligands were identified and evaluated for pharmacokinetic properties, with four compounds showing the most desired profile. Molecular dynamics studies suggested stability of these compounds, particularly ZINC02639178, which may be a potential treatment option pending further experimental studies.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2022)
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
Gehad Lotfy, Yasmine M. Abdel Aziz, Mohamed M. Said, El Sayed H. El Ashry, El Sayed H. El Tamany, Marwa M. Abu-Serie, Mohamed Teleb, Alexander Domling, Assem Barakat
Summary: Combination of MDM2 and BCL2 inhibition can sensitize tumor cells and induce apoptosis synergistically. Novel MDM2 inhibitors 5i and 5q showed promising anticancer activities and apoptosis induction effects in cancer cells in vitro tests.
BIOORGANIC CHEMISTRY
(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, Multidisciplinary
Akiko Fujimura, Hisashi Ishida, Tamiko Nozaki, Shuhei Terada, Yuto Azumaya, Tadashi Ishiguro, Yugo R. Kamimura, Tomoya Kujirai, Hitoshi Kurumizaka, Hidetoshi Kono, Kenzo Yamatsugu, Shigehiro A. Kawashima, Motomu Kanai
Summary: Peptides can be modified and used as ligands for targeting proteins of interest by inserting them into fusion proteins. This study demonstrates the use of a peptide ligand-inserted fusion protein as a universal adaptor for targeting proteins with cell-permeable and stable small molecules. By using specific small molecules, post-translational modifications can be targeted to specific residues on the proteins.
ACS CENTRAL SCIENCE
(2023)
Article
Oncology
Qian Zhao, Shan-Shan Xiong, Can Chen, Hong-Ping Zhu, Xin Xie, Cheng Peng, Gu He, Bo Han
Summary: The authors designed and synthesized a series of compounds with dual inhibitory activity against MDM2 and HDAC, and found that compound 11b exhibited the strongest inhibition against both targets. This compound also showed effective antiproliferative activity towards MCF-7 cells and increased the expression of p53 and Ac-H4. These results suggest that dual inhibition of HDAC and MDM2 may provide a novel and efficient strategy for the discovery of antitumor drugs in the future.
FRONTIERS IN ONCOLOGY
(2022)
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
Medicine, Research & Experimental
Xudong Wang, Yanshi Li, Min Pan, Tao Lu, Min Wang, Zhihai Wang, Chuan Liu, Guohua Hu
Summary: This study explored the role of CEA family member 5 (CEACAM5) in head and neck squamous cell carcinoma (HNSCC). The results showed a close association between CEACAM5 levels and lymph node (LN) metastasis, and high CEACAM5 levels had a positive impact on clinical prognosis. Experimental findings demonstrated that CEACAM5 inhibited cell proliferation and migration, and promoted apoptosis to suppress LN metastasis. Therefore, CEACAM5 has potential as both a prognostic marker and a therapeutic target in HNSCC.
Article
Chemistry, Medicinal
Michael H. Reutershan, Michelle R. Machacek, Michael D. Altman, Stephane Bogen, Mingmei Cai, Carolyn Cammarano, Dapeng Chen, Matthew Christopher, John Cryan, Pierre Daublain, Xavier Fradera, Prasanthi Geda, Peter Goldenblatt, Armetta D. Hill, Raymond A. Kemper, Victoria Kutilek, Chaomin Li, Michelle Martinez, Mark McCoy, Latha Nair, Weidong Pan, Christopher F. Thompson, Giovanna Scapin, Manami Shizuka, Marianne L. Spatz, Dietrich Steinhuebel, Binyuan Sun, Matthew E. Voss, Xiao Wang, Liping Yang, Tammie C. Yeh, Isabelle Dussault, C. Gary Marshall, B. Wesley Trotter
Summary: Identifying low-dose, low-molecular-weight, drug-like inhibitors of protein-protein interactions is challenging yet important. By leveraging known binding hot spots and biostructural information, researchers successfully optimized a novel purine carboxylic acid-derived inhibitor into a series of low-projected dose inhibitors with favorable pharmacokinetic and physical properties, leading to the discovery of a highly potent, selective, and low-molecular-weight inhibitor suitable for clinical investigation.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Maksim Kukushkin, Vladimir Novotortsev, Vadim Filatov, Yan Ivanenkov, Dmitry Skvortsov, Mark Veselov, Radik Shafikov, Anna Moiseeva, Nikolay Zyk, Alexander Majouga, Elena Beloglazkina
Summary: A series of novel dispirooxindole derivatives containing S, O, and Se were synthesized and showed good cytotoxicity and selectivity towards colorectal carcinoma cells. Computational study suggested MDM2/p53 interaction as a possible target, but in vitro experiments did not observe significant p53 activation within a relevant concentration range.
Article
Biochemistry & Molecular Biology
Ravi Tripathi, Abiodun Anifowose, Wen Lu, Xiaoxiao Yang, Binghe Wang
Summary: By optimizing the substituents on the two phenol hydroxyl groups, we have discovered a potent series of anthraquinone analogs that exert cytotoxicity by inducing MDM2 degradation and upregulating p53. Among them, BW-AQ-350 is the most potent compound with high cytotoxic activity.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2022)
Review
Oncology
Haohao Zhu, Hui Gao, Yingying Ji, Qin Zhou, Zhiqiang Du, Lin Tian, Ying Jiang, Kun Yao, Zhenhe Zhou
Summary: p53, encoded by TP53 gene, is a crucial tumor suppressor and can be regulated by MDM2 through negative feedback loop. Inhibiting MDM2 to restore p53 function is a hot topic in anticancer drug development. This review focuses on the discovery, structural modification, preclinical and clinical research of MDM2 inhibitors and analyzes the potential defects in their clinical development.
JOURNAL OF HEMATOLOGY & ONCOLOGY
(2022)
Article
Multidisciplinary Sciences
Jing Zhao, Alan Blayney, Xiaorong Liu, Lauren Gandy, Weihua Jin, Lufeng Yan, Jeung-Hoi Ha, Ashley J. Canning, Michael Connelly, Chao Yang, Xinyue Liu, Yuanyuan Xiao, Michael S. Cosgrove, Sozanne R. Solmaz, Yingkai Zhang, David Ban, Jianhan Chen, Stewart N. Loh, Chunyu Wang
Summary: Epigallocatechin gallate (EGCG) in green tea induces apoptosis in cancerous cells through a direct interaction with the tumor suppressor p53, inhibiting p53 ubiquitination by its regulatory E3 ligase MDM2 and stabilizing p53 for anti-tumor activity.
NATURE COMMUNICATIONS
(2021)