HDM-MDM
The vast majority of p53-regulated genes are induced in response to various stress signals and are responsible for maintaining genetic stability, DNA repair, regulation of crucial cell-cycle check points, and finally induction of apoptosis. The activity of p53 is tightly controlled by two major negative regulators including murine double minute 2 (MDM2; EC 6.3.2.19) and 4 (MDM4 or MDMX) proteins. Human MDM2 and MDMX are structurally related and contain three well-conserved domains: an N-terminal domain (responsible for p53 binding), a zinc-finger domain (function largely unknown) and a C-terminal RING domain (responsible for formation of homo- and heterodimers). Additionally, the RING domain of MDM2 confers E3 ubiquitin ligase activity. Concentration/activity of p53 is kept at low level in unstressed cells. This is accomplished by three parallel mechanisms mediated by MDM2 and/or MDMX. First, MDM2 and MDMX bind the N-terminal transactivation domain (TAD) of p53, preventing thereby its interaction with the transcription machinery and resulting in the inhibition of p53-responsive gene expression. Second, MDM2/X proteins export p53 outside the nucleus into the cytoplasm where it can no longer activate transcription. Finally, MDM2 marks p53 for proteasomal degradation[1]. Many tumors overproduce MDM2 to impair p53 function. Therefore, restoration of p53 activity by inhibiting the p53–MDM2 binding represents an attractive novel approach to cancer therapy[2].
[1] K. Zak et al. Mdm2 and MdmX inhibitors for the treatment of cancer: a patent review (2011 – present). Exp. Opin. Ther. Pat. 2013, 23, 425-448.
[2] B.T. Vu, L. Vassilev. Small-Molecule Inhibitors of the p53-MDM2 Interaction. Curr. Top. Microbiol. Immun. 2011, 348, 151-172.
Axon ID | Name | Description | From price | |
---|---|---|---|---|
2437 | SP 141 | Specific MDM2 inhibitor with therapeutic effects in breast cancer models | €120.00 | |
2164 | SJ 172550 | Small molecule inhibitor of MDMX | €95.00 | |
3737 | Siremadlin | Potent, selective, and orally bioavailable MDM2-p53 inhibitor | €130.00 | |
2741 | SAR405838 | MDM2-p53 inhibitor | €125.00 | |
2009 | RITA | Activates p53 through inhibition of MDM2 | €105.00 | |
4035 | RG-7388 | Potent and selective MDM2 antagonist | Inquire | |
3752 | NVP-CGM097 dihydrochloride | Inhibitor of MDM2 | Inquire | |
3751 | NVP-CGM097 | Inhibitor of MDM2 | Inquire | |
1881 | Nutlin-3b | Less potent (+)-enantiomer of Nutlin-3 | €90.00 | |
1880 | Nutlin-3a | Inhibitor of MDM2 | €95.00 | |
1585 | Nutlin-3 | MDM2 inhibitor (p53 specific) | €95.00 | |
1586 | JNJ 26854165 dihydrochloride | HDM2 inhibitor | €105.00 | |
1538 | JNJ 26854165 | HDM2 inhibitor | €105.00 | |
1643 | HLI 373 | HDM2 inhibitor | €100.00 | |
3765 | DS-3032 | Orally available, potent and selective inhibitor of the p53-MDM2 interaction | Inquire | |
2639 | AMG 232 | Potent, selective, and orally bioavailable MDM2-p53 inhibitor | €120.00 |