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Precision medicine in ovarian carcinoma
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Shailendra Dwivedi, Purvi Purohit, Radhieka Misra, Jeewan Ram Vishnoi, Apul Goel, Puneet Pareek, Sanjay Khattri, Praveen Sharma, Sanjeev Misra, Kamlesh Kumar Pant
Recently Zanjirband et al. (2016) analyzed combination therapy of Nutlin-3 with cisplatin. They demonstrated in ovarian cancer cell lines that Nutlin-3 or RG7388 effect in combination with cisplatin was additive to or synergistic in a p53-dependent manner, resulting in increased p53 activation, cell cycle arrest, and apoptosis, associated with increased p21WAF1 protein and/or caspase-3/7 activity compared to cisplatin alone.
Microarrays: Human Disease Detection and Monitoring
Published in Attila Lorincz, Nucleic Acid Testing for Human Disease, 2016
Janet A. Warrington, Thomas B. Broudy
The nutlin compound works by projecting three chemical groups into the MDM2 pockets normally occupied by Phe 19, Trp 23, and Leu 26 of p53 (Figure 3.10). Depending on the genetic variation in the patient’s p53 gene, the competitive nutlin inhibition may be variable, potentially requiring a dosage adjustment for optimal treatment. Naturally, using microarrays to examine variations in the MDM2 gene itself, especially in the p53 binding pocket, may help correlate MDM2 genetic variation to nutlin treatment outcome.
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
A number of inhibitors of the MDM2-p53 interaction were then discovered by screening chemically diverse libraries using enzyme-linked immunosorbent and fluorescence-based cell-free assays. One of the best-known classes was discovered by Roche and called the “nutlins”, named after the location of the research team in Nutley, New Jersey (USA). The most active of these molecules, nutlin-2 (Figure 6.102A) and nutlin-3, have in vitro potencies (i.e., IC50 values) in some cell lines in the order of 0.14 µM and 0.09 µM, respectively. Molecular modeling studies confirmed the good fit of the nutlin molecules in a cleft on the p53-interactive surface of the MDM2 protein (Figure 6.102B). Biochemical studies confirmed that the nutlins induce the expression of p53-regulated genes and exhibit their antiproliferative activity through the induction of apoptosis in cancer cells expressing wild-type (i.e., functional) p53 but not in cells with mutated p53. At least one nutlin analog, nutlin-3, was found to have acceptable pharmacokinetic properties and demonstrated antitumor activity in human tumor xenograft mouse models, reducing tumor growth by 90% but at the relatively high dose of 200 mg/kg. However, at the time, these results stimulated a growing interest in this class of agents in both academic and industrial laboratories. A. Structure of nutlin-2, the first MDM2-p53 inhibitor to be discovered; B. View of the crystal structure of the complex of nutlin-MDM2, showing the nutlin-2 molecule bound in a hydrophobic cleft of the protein (Kindly provided by Professor Stephen Neidle).
Targeting p53 in chronic lymphocytic leukemia
Published in Expert Opinion on Therapeutic Targets, 2020
Riccardo Moia, Paola Boggione, Abdurraouf Mokhtar Mahmoud, Ahad Ahmed Kodipad, Ramesh Adhinaveni, Sruthi Sagiraju, Andrea Patriarca, Gianluca Gaidano
The p53 protein is highly regulated by different molecules that control its activity. MDM2 is an E3 ubiquitin ligase that controls the half-life of p53 via ubiquitin-dependent proteasomal degradation (Figure 3) [13,80]. In response to cellular stress, the p53-MDM2 interaction is disrupted, and p53 can exert its function by activating the transcription of target genes that trigger cell cycle arrest and apoptosis [81]. Since the discovery of the first selective MDM2 inhibitor, i.e. the Nutlin-3a small molecule, newer compounds have been developed with increased potency and improved bioavailability [82,83]. These non-genotoxic compounds bind to MDM2 in the p53-binding pocket and can release p53, leading to effective stabilization of the protein and activation of the Tp53 pathway (Figure 4) [82,83]. Initial preclinical and clinical studies have demonstrated promising efficacy of this class of drugs in a number of TP53 wild type adult and pediatric cancers, both as single agents and in combination with other targeted therapies [84–90].
Genomic-based treatment of patients with head and neck cancer
Published in Expert Review of Precision Medicine and Drug Development, 2020
Arpan Patel, Seyed Mohammad Abedi, Manidhar Lekkala, Megan Baumgart
Mutations in tumor suppressor genes TP53, FAT atypical cadherin 1 (FAT1), and NOTCH1 are found in approximately 80% of HNSCC tumors, and EGFR overexpression and PTEN inactivation are also frequently found [2]. Activity of p53 is controlled by MDM2, which plays a key role in p53 ubiquitination. Given the frequency of TP53 mutations, there has been interest in trying to identify therapies that restore gene function or may enhance p53 activity. Nutlin-3 is a small-molecule p53-MDM2 binding inhibitor. Nutlin-3, in addition to other inhibitors of p53-MDM2, MI-219, and RITA (Reactivation of p53 and Induction of Tumor cell Apoptosis), have been evaluated in p53 wild type cell lines with varying response. Nutlin-3 has been shown to result in cell cycle arrest in p53 wild type cells. It has been proposed that treating patients with p53-mutated tumors with Nutlin-3 may result in cell cycle arrest in non-tumor cells, thereby shielding them from chemotherapy, as they are not dividing [23]. No clinical data regarding this approach are currently available.
An expert overview of emerging therapies for acute myeloid leukemia: novel small molecules targeting apoptosis, p53, transcriptional regulation and metabolism
Published in Expert Opinion on Investigational Drugs, 2020
Kapil Saxena, Marina Konopleva
MDM2 can be inhibited by a class of small molecule inhibitors called nutlins. Nutlins bind MDM2 in its p53-binding pocket, thereby preventing MDM2 from binding p53 [43]. Nutlin-3a, a first-generation nutlin, was initially shown to decrease cell proliferation and increase p53-mediated apoptosis in several AML cell lines and primary patient samples with wild-type p53 [43]. Nutlin binding is largely restricted to wild-type p53; nutlins do not bind mutated p53 effectively and have minimal effect on proliferation of p53-mutated AML cells [43]. However, first-generation nutlins exhibited poor bioavailability and underwent limited clinical development [44]. RG7388, also known as idasanutlin, is a second-generation nutlin that shows improved pharmacokinetics and bioavailability compared to first-generation nutlins (Figure 2) [45,50]. Like Nutlin-3a, idasanutlin also increases apoptosis of wild-type p53 AML cells, but not of p53-mutated AML cells [45].