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MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer
- Source :
- Journal of Hematology & Oncology, Vol 10, Iss 1, Pp 1-17 (2017), Journal of Hematology & Oncology
- Publication Year :
- 2017
- Publisher :
- BMC, 2017.
-
Abstract
- The two murine double minute (MDM) family members MDM2 and MDMX are at the center of an intense clinical assessment as molecular target for the management of cancer. Indeed, the two proteins act as regulators of P53, a well-known key controller of the cell cycle regulation and cell proliferation that, when altered, plays a direct role on cancer development and progression. Several evidence demonstrated that functional aberrations of P53 in tumors are in most cases the consequence of alterations on the MDM2 and MDMX regulatory proteins, in particular in patients with hematological malignancies where TP53 shows a relatively low frequency of mutation while MDM2 and MDMX are frequently found amplified/overexpressed. The pharmacological targeting of these two P53-regulators in order to restore or increase P53 expression and activity represents therefore a strategy for cancer therapy. From the discovery of the Nutlins in 2004, several compounds have been developed and reported with the ability of targeting the P53-MDM2/X axis by inhibiting MDM2 and/or MDMX. From natural compounds up to small molecules and stapled peptides, these MDM2/X pharmacological inhibitors have been extensively studied, revealing different biological features and different rate of efficacy when tested in in vitro and in vivo experimental tumor models. The data/evidence coming from the preclinical experimentation have allowed the identification of the most promising molecules and the setting of clinical studies for their evaluation as monotherapy or in therapeutic combination with conventional chemotherapy or with innovative therapeutic protocols in different tumor settings. Preliminary results have been recently published reporting data about safety, tolerability, potential side effects, and efficacy of such therapeutic approaches. In this light, the aim of this review is to give an updated overview about the state of the art of the clinical evaluation of MDM2/X inhibitor compounds with a special attention to hematological malignancies and to the potential for the management of pediatric cancers.
- Subjects :
- 0301 basic medicine
Cancer Research
Indoles
Pyrrolidines
MDMX
Cell Cycle Proteins
Review
Pharmacology
0302 clinical medicine
para-Aminobenzoates
Molecular Targeted Therapy
Protein Interaction Maps
Child
Hematology
Leukemia
biology
Nuclear Proteins
Proto-Oncogene Proteins c-mdm2
lcsh:Diseases of the blood and blood-forming organs
Cell cycle
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Clinical studies, Leukemia, MDM2, MDMX, Pediatric tumors, Pharmacological inhibitor
Oncology
Tolerability
Hematologic Neoplasms
030220 oncology & carcinogenesis
Pharmacological inhibitor
Mdm2
Signal Transduction
medicine.medical_specialty
Antineoplastic Agents
Pediatric tumors
lcsh:RC254-282
NO
03 medical and health sciences
MDM2
In vivo
Proto-Oncogene Proteins
Internal medicine
medicine
Animals
Humans
Spiro Compounds
Imidazolines
Molecular Biology
business.industry
lcsh:RC633-647.5
Cancer
medicine.disease
Pediatric cancer
030104 developmental biology
Cancer research
biology.protein
Tumor Suppressor Protein p53
business
Clinical studies
Subjects
Details
- Language :
- English
- ISSN :
- 17568722
- Volume :
- 10
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Journal of Hematology & Oncology
- Accession number :
- edsair.doi.dedup.....a679f4dadd13959b87ea3ea45dfd17ce