1.Lead Optimization of 2-Phenylindolylglyoxylyldipeptide Murine Double Minute (MDM)2/Translocator Protein (TSPO) Dual Inhibitors for the Treatment of Gliomas.
Daniele S, La Pietra V, Barresi E, Di Maro S, Da Pozzo E, Robello M, La Motta C, Cosconati S, Taliani S, Marinelli L, Novellino E, Martini C, Da Settimo F. J Med Chem. 2016 Apr 6. [Epub ahead of print]
In Glioblastoma Multiforme (GBM), Translocator Protein (TSPO) and Murine Double Minute (MDM2)/p53 represent two druggable targets. We recently reported the first dual binder 3 possessing a higher anticancer effect in GBM cells than the standards PK11195 1 or Nutlin-3 2 singularly applied. Herein, through a Structure-Activity-Relationship study, we developed derivatives 4-10 with improved potencies toward both TSPO and MDM2. As a result, compound 9: (i) reactivated the p53 functionality; (ii) inhibited viability of two human GBM cells; (iii) impaired the proliferation of glioma cancer stem cells (CSCs), more resistant to chemotherapeutics, and responsible of GBM recurrence; (iv) sensitized GBM cells and CSCs to the activity of Temozolomide; (v) directed its effects preferentially toward tumour cells with respect to healthy ones. Thus, 9 may represent a promising cytotoxic agent which is worthy to be further developed for a therapeutic approach against GBM, where the downstream p53 signalling is intact and TSPO is over-expressed.
2.Integrative modeling of multi-omics data to identify cancer drivers and infer patient-specific gene activity.
Pavel AB1,2, Sonkin D3, Reddy A4. BMC Syst Biol. 2016 Feb 11;10(1):16. doi: 10.1186/s12918-016-0260-9.
BACKGROUND: High throughput technologies have been used to profile genes in multiple different dimensions, such as genetic variation, copy number, gene and protein expression, epigenetics, metabolomics. Computational analyses often treat these different data types as independent, leading to an explosion in the number of features making studies under-powered and more importantly do not provide a comprehensive view of the gene's state. We sought to infer gene activity by integrating different dimensions using biological knowledge of oncogenes and tumor suppressors.
3.Chemical Inhibition of Wild-Type p53-Induced Phosphatase 1 (WIP1/PPM1D) by GSK2830371 Potentiates the Sensitivity to MDM2 Inhibitors in a p53-Dependent Manner.
Esfandiari A1, Hawthorne TA1, Nakjang S2, Lunec J3. Mol Cancer Ther. 2016 Mar;15(3):379-91. doi: 10.1158/1535-7163.MCT-15-0651. Epub 2016 Feb 1.
Sensitivity to MDM2 inhibitors is widely different among responsive TP53 wild-type cell lines and tumors. Understanding the determinants of MDM2 inhibitor sensitivity is pertinent for their optimal clinical application. Wild-type p53-inducible phosphatase-1 (WIP1) encoded by PPM1D, is activated, gained/amplified in a range of TP53 wild-type malignancies, and is involved in p53 stress response homeostasis. We investigated cellular growth/proliferation of TP53 wild-type and matched mutant/null cell line pairs, differing in PPM1D genetic status, in response to Nutlin-3/RG7388 ± a highly selective WIP1 inhibitor, GSK2830371. We also assessed the effects of GSK2830371 on MDM2 inhibitor-induced p53(Ser15) phosphorylation, p53-mediated global transcriptional activity, and apoptosis. The investigated cell line pairs were relatively insensitive to single-agent GSK2830371. However, a non-growth-inhibitory dose of GSK2830371 markedly potentiated the response to MDM2 inhibitors in TP53 wild-type cell lines, most notably in those harboring PPM1D-activating mutations or copy number gain (up to 5.
4.Monitoring Ligand-Induced Protein Ordering in Drug Discovery.
Grace CR1, Ban D1, Min J2, Mayasundari A2, Min L1, Finch KE3, Griffiths L4, Bharatham N1, Bashford D1, Kiplin Guy R2, Dyer MA5, Kriwacki RW6. J Mol Biol. 2016 Mar 27;428(6):1290-303. doi: 10.1016/j.jmb.2016.01.016. Epub 2016 Jan 23.
While the gene for p53 is mutated in many human cancers causing loss of function, many others maintain a wild-type gene but exhibit reduced p53 tumor suppressor activity through overexpression of the negative regulators, Mdm2 and/or MdmX. For the latter mechanism of loss of function, the activity of endogenous p53 can be restored through inhibition of Mdm2 or MdmX with small molecules. We previously reported a series of compounds based upon the Nutlin-3 chemical scaffold that bind to both MdmX and Mdm2 [Vara, B. A. et al. (2014) Organocatalytic, diastereo- and enantioselective synthesis of nonsymmetric cis-stilbene diamines: A platform for the preparation of single-enantiomer cis-imidazolines for protein-protein inhibition. J. Org. Chem. 79, 6913-6938]. Here we present the first solution structures based on data from NMR spectroscopy for MdmX in complex with four of these compounds and compare them with the MdmX:p53 complex. A p53-derived peptide binds with high affinity (Kd value of 150nM) and causes the formation of an extensive network of hydrogen bonds within MdmX; this constitutes the induction of order within MdmX through ligand binding.
CAS No.: 548472-68-0
Purity: >98%
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