Journal: Sub-cellular biochemistry

Article Title: Targeting p53-MDM2-MDMX Loop for Cancer Therapy

doi: 10.1007/978-94-017-9211-0_16

Figure Lengend Snippet: Inhibitors targeting MDM2-MDMX loop discovered by different strategies

Article Snippet: Over the past decade, a number of new small molecules in addition to the previously reported Nutlin-3 [ 44 ] have been identified to target either MDM2 or MDMX or both in this pathway, some of which as listed in have been further advanced to the stage of clinical trials. table ft1 table-wrap mode="anchored" t5 caption a7 Small molecule Status ID Scaffold Discover methods K i or IC 50 In vivo test Reference M2-p53 interaction a Preclinical Nutlin-3 c Imidazolines HTS, SPR assay ~0.1 µM Retinoblastoma [ 44 ] Phase I RG7112 (RO5045337) 18 nM Advanced malignancies, except leukemia [ 100 ] M2-p53 interaction Preclinical MI63, MI-219 Spirooxindoles Structure-based design ~1–50 nM SJSA-1 xenograft [ 94 ] Phase I MI-773 (SAR405838) Advanced cancer [ 63 ] M2-p53 interaction NSC333003 c Benzothiazoles Virtual screening ~20 µM [ 150 ] M2-p53 interaction Preclinical TPD222669 Benzodiazepines HTS ThermoFlor 0.08 µM A3 7 5 xenograft [ 151 ] M2-p53 interaction Preclinical YH265 Pyrazoles HCS, Biosensor 1.8 µM NCI60 cancer cells [ 83 , 84 ] WO2011106650 M2-p53 interaction Phase I CGM097 (Novartis) <50 nM Selected advanced and refractory solid tumors [ 63 ] M2-p53 interaction Phase I MK-8242 (Merck) Piperidines [ 63 ] M2-p53 interaction Preclinical PXN727 (Priaxon) Isoquinoline-1-ones, pyrrolinones Virtual screening 8 nM-1 µM LNCaP xenograft http://www.priaxon.com/content/_docs/docl264519272209.pdf M2-p53 interaction Tetra-substituted heteroaryls Structure-based design 1 nM-50 µM [ 63 ] M2-p53 interaction c Substituted pyrazoles Structure-based design M2: ~0.02 µM; MX: ~10 µM M2-p53 interaction c Indole-2-carboxylic acids Structure-based design 130–400 nM M2-p53 interaction Indolinones Structure-based design 1.2nM-3.7nM M2-p53 interaction Piperidines Structure-based design 0.02–0.27 µM M2-p53 interaction Preclinical AM-8553 Piperidinones Structure-based design 150 nM SJSA xenograft [ 96 ] M2-p53 interaction Preclinical Pyrrolidone Virtual screening, FP assay 0.26 µM A549 xenograft [ 152 ] MX-p53 interaction b Preclinical SJ-172550 c SJ000558295 Imidazolines HTS,FP assay HTS.FP ~1 µM M2:9.1 µM; MX: ~9.0 µM Retinoblastoma cells [ 59 ] [ 63 ] Preclinical SJ000558304 HTS.FP M2:>150nM; MX: ~2 µM MX-p53 interaction XI-006 Benzofuroxans HCS, luciferase reporter assay MCF-7 cells [ 60 ] Dual inhibitor Preclinical RO-2443, RO-5963 c Indolyl Hydantoins HTS,TR-FRET Assay M2 and MX: <50 nM MCF7, HCT, RKO cells [ 61 ] Dual inhibitor?

Techniques: In Vivo, SPR Assay, FP Assay, Luciferase, Reporter Assay, Cell Based Assay