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
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.
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
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.
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)
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
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
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
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
Mayu Nakagawa, Shyoma Higuchi, Miki Hashimura, Yasuko Oguri, Toshihide Matsumoto, Ako Yokoi, Yu Ishibashi, Takashi Ito, Makoto Saegusa
Summary: The study suggests that the interaction between S100A1 and MDM2 may modulate proliferation, susceptibility to apoptosis, and migration through alterations in p53 signaling in normal endometrial cells. However, such correlations were absent in malignant endometrial cells.
Article
Cell Biology
Yiyang Sun, Lingling Zhang, Zhuoqing Fang, Dingyu Liu, Min Shao, Yujie Liu, Bing Liao, Ying Jin
Summary: The PRPF8 gene is essential for the survival of human embryonic stem cells (hESCs). Knockdown of PRPF8 induces p53 accumulation and activates the p53 pathway, leading to apoptosis in hESCs. PRPF8 regulates alternative splicing of PIRH2 to maintain p53 pathway activity and hESC survival.
JOURNAL OF CELLULAR PHYSIOLOGY
(2023)
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
Biochemistry & Molecular Biology
Emilia Barrio, Rebeca Vecino, Irene Sanchez-Moran, Cristina Rodriguez, Alberto Suarez-Pindado, Juan P. Bolanos, Angeles Almeida, Maria Delgado-Esteban
Summary: The study identified that ischemic preconditioning induces activation of the PI3K/AKT signaling pathway, promoting neuronal tolerance by controlling the MDM2-p53 interaction. These findings offer a novel mechanistic pathway for IPC-induced neuroprotection, suggesting that AKT could be a potential therapeutic target against ischemic injury.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
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
Oncology
Rui Shi, Zirong Liu
Summary: RPL15 plays crucial roles in the progression and metastasis of hepatocellular carcinoma (HCC), serving as a promising candidate for targeted therapies.
CANCER CELL INTERNATIONAL
(2022)
Article
Biochemistry & Molecular Biology
Vincenzo A. Gennarino, Ravi K. Singh, Joshua J. White, Antonia De Maio, Kihoon Han, Ji-Yoen Kim, Paymaan Jafar-Nejad, Alberto di Ronza, Hyojin Kang, Layal S. Sayegh, Thomas A. Cooper, Harry T. Orr, Roy V. Sillitoe, Huda Y. Zoghbi
Article
Biochemistry & Molecular Biology
Simona Pedrotti, Jimena Giudice, Adan Dagnino-Acosta, Mark Knoblauch, Ravi K. Singh, Amy Hanna, Qianxing Mo, John Hicks, Susan Hamilton, Thomas A. Cooper
HUMAN MOLECULAR GENETICS
(2015)
Article
Biochemistry & Molecular Biology
Daniel F. Comiskey, Aishwarya G. Jacob, Ravi K. Singh, Aixa S. Tapia-Santos, Dawn S. Chandler
NUCLEIC ACIDS RESEARCH
(2015)
Letter
Oncology
G. Palacios, T. I. Shaw, Y. Li, R. K. Singh, M. Valentine, J. T. Sandlund, M. S. Lim, C. G. Mullighan, V. Leventaki
Article
Cell Biology
Fuad Mohammad, Christopher J. Woolstenhulme, Rachel Green, Allen R. Buskirk
Article
Cell Biology
Ravi K. Singh, Arseniy M. Kolonin, Marta L. Fiorotto, Thomas A. Cooper
Article
Biochemistry & Molecular Biology
Aishwarya G. Jacob, Ravi K. Singh, Fuad Mohammad, Thomas W. Bebee, Dawn S. Chandler
JOURNAL OF BIOLOGICAL CHEMISTRY
(2014)
Article
Biochemistry & Molecular Biology
Ravi K. Singh, Zheng Xia, Christopher S. Bland, Auinash Kalsotra, Marissa A. Scavuzzo, Tomaz Curk, Jernej Ule, Wei Li, Thomas A. Cooper
Article
Cell Biology
Auinash Kalsotra, Ravi K. Singh, Priyatansh Gurha, Amanda J. Ward, Chad J. Creighton, Thomas A. Cooper
Editorial Material
Hematology
Dylan Graetz, Kristine R. Crews, Elizabeth M. Azzato, Ravi K. Singh, Susana Raimondi, John Mason, Marcus Valentine, Charles G. Mullighan, Ashley Holland, Hiroto Inaba, Vasiliki Leventaki
Article
Microbiology
Jeremy Weaver, Fuad Mohammad, Allen R. Buskirk, Gisela Storz
Article
Biology
Fuad Mohammad, Rachel Green, Allen R. Buskirk
Article
Oncology
Dan F. Comiskey, Matias Montes, Safiya Khurshid, Ravi K. Singh, Dawn S. Chandler
MOLECULAR CANCER RESEARCH
(2020)