Blocking the MDM2-p53 protein-protein interaction has long been considered to offer a broad cancer therapeutic strategy, despite the potential risks of selecting tumors harboring p53 mutations that escape MDM2 control. In this study, we report a novel small molecule inhibitor of the MDM2-p53 interaction, SAR405838 (MI-77301) that has been advanced into Phase I clinical trials. SAR405838 binds to MDM2 with Ki = 0.88 nM and has high specificity over other proteins. A co-crystal structure of the SAR405838:MDM2 complex shows that in addition to mimicking three key p53 amino acid residues, the inhibitor captures additional interactions not observed in the p53-MDM2 complex and induces refolding of the short, unstructured MDM2 N-terminal region to achieve its high affinity. SAR405838 effectively activates wild-type p53 in vitro and in xenograft tumor tissue of leukemia and solid tumors, leading to p53-dependent cell cycle arrest and/or apoptosis. At well-tolerated dose schedules, SAR405838 achieves either durable tumor regression or complete tumor growth inhibition in mouse xenograft models of SJSA-1 osteosarcoma, RS4;11 acute leukemia, LNCaP prostate cancer and HCT-116 colon cancer. Remarkably, a single oral dose of SAR405838 is sufficient to achieve complete tumor regression in the SJSA-1 model. Mechanistically, robust transcriptional up-regulation of PUMA induced by SAR405838 results in strong apoptosis in tumor tissue, leading to complete tumor regression. Our findings provide a preclinical basis upon which to evaluate SAR405838 as a therapeutic agent in patients whose tumors retain wild-type p53.

We previously reported the discovery of a class of spirooxindoles as potent and selective small-molecule inhibitors of the MDM2-p53 interaction (MDM2 inhibitors). We report herein our efforts to improve their pharmacokinetic properties and in vivo antitumor activity. Our efforts led to the identification of 9 (MI-888) as a potent MDM2 inhibitor (Ki = 0.44 nM) with a superior pharmacokinetic profile and enhanced in vivo efficacy. Compound 9 is capable of achieving rapid, complete, and durable tumor regression in two types of xenograft models of human cancer with oral administration and represents the most potent and efficacious MDM2 inhibitor reported to date.

Small-molecule inhibitors that block the MDM2-p53 protein-protein interaction (MDM2 inhibitors) are being intensely pursued as a new therapeutic strategy for cancer treatment. We previously published a series of spirooxindole-containing compounds as a new class of MDM2 small-molecule inhibitors. We report herein a reversible ring opening-cyclization reaction for some of these spirooxindoles, which affords four diastereomers from a single compound. Our biochemical binding data showed that the stereo-chemistry in this class of compounds has a major effect on their binding affinities to MDM2; with >100-fold difference between the most potent and the least potent stereoisomers. Our study has led to the identification of a set of highly potent MDM2 inhibitors with a stereochemistry that is different from that of our previously reported compounds. The most potent compound (MI-888) binds to MDM2 with a Ki value of 0.44 nM and achieves complete and long-lasting tumor regression in an animal model of human cancer.

We report herein the design of potent and orally active small-molecule inhibitors of the MDM2-p53 interaction. Compound 5 binds to MDM2 with a K i value of 0.6 nM, activates p53 at concentrations as low as 40 nM, and potently and selectively inhibits cell growth in tumor cells with wild-type p53 over tumor cells with mutated/deleted p53. Compound 5 has a good oral bioavailability and effectively inhibits tumor growth in the SJSA-1 xenograft model. The p53 tumor suppressor is an attractive cancer therapeutic target because its tumor suppressor activity can be stimulated to eradicate tumor cells. [1][2][3] In tumor cells with wild-type p53, the p53 activity is effectively inhibited by its endogenous inhibitor, the human MDM2 protein, through direct binding to p53. 4,5 The interaction site between MDM2 and p53 proteins is mediated by a well-defined pocket in MDM2 and a short helix from p53, making this site attractive for the design of small-molecule inhibitors to block the MDM2-p53 protein-protein interaction. 6,7 Reactivation of p53 by blocking the MDM2-p53 interaction using a smallmolecule inhibitor is being pursued as an exciting, new cancer therapeutic strategy. [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] We have recently reported the design of spiro-oxindoles as a new class of potent, selective, cell permeable, non-peptidic, small-molecule inhibitors of the MDM2-p53 interaction. 9-11 Using a structure-based approach, we have obtained compound 1 (MI-63, Figure 1) as a potent and cell-permeable MDM2 inhibitor. Compound 1 binds to MDM2 protein with a low nanomolar affinity in our fluorescence-polarization (FP) based, competitive, biochemical binding assay. 10 Consistent with its mode of action, compound 1 potently inhibits cell growth in cancer cells with wild-type p53 and is selective over cancer cells with mutated/deleted p53. In our subsequent pharmacokinetic (PK) evaluations, compound 1 was found to have a poor PK profile and a modest oral bioavailability ( Analysis of the predicted binding model for 1 showed that the morpholinyl group is partially exposed to solvent. 10 This suggested that the morpholinyl group in 1 may be replaced by other groups without a detrimental effect on binding to MDM2 and cellular activity. We have therefore carried out chemical modifications of this region to investigate the structure-activity relationship on binding, cellular activity and PK parameters.We first designed and synthesized compounds 2 and 3 (Figure 1), in which the morpholinyl group in compound 1 is replaced by a methylpiperazinyl group or a methylpiperidinyl group, respectively. Our binding experiments showed that these two compounds bind to MDM2 with K i values of 1.5 and 2.0 nM, respectively (Table 1). Consistent with their high binding affinities to MDM2, they potently inhibit cell growth in the cancer cell lines with wild-type p53, and display excellent selectivity over cancer cell lines with deleted p53 (Table 1 and Supporting Information). However, PK testing showed that while compounds...

External stimulation, mood swing, and physiological arousal are closely related and induced by each other. The exploration of internal relations between these three aspects is interesting and significant. Currently, video is the most popular multimedia stimuli that can express rich emotional semantics by its visual and auditory features. Apart from the video features, human electroencephalography (EEG) features can provide useful information for video emotion recognition, as they are the direct and instant authentic feedback on human perception with individuality. In this paper, we collected a total of 39 participants' EEG data induced by watching emotional video clips and built a fusion dataset of EEG and video features. Subsequently, the machine-learning algorithms, including Liblinear, REPTree, XGBoost, MultilayerPerceptron, RandomTree, and RBFNetwork were applied to obtain the optimal model for video emotion recognition based on a multi-modal dataset. We discovered that using the data fusion of all-band EEG power spectrum density features and video audio-visual features can achieve the best recognition results. The video emotion classification accuracy achieves 96.79% for valence (Positive/Negative) and 97.79% for arousal (High/Low).The study shows that this method can be a potential method of video emotion indexing for video information retrieval.