Restoration of p53 activity by inhibition of the p53-MDM2 interaction has been considered an attractive approach for cancer treatment. However, the hydrophobic protein-protein interaction surface represents a significant challenge for the development of small-molecule inhibitors with desirable pharmacological profiles. RG7112 was the first small-molecule p53-MDM2 inhibitor in clinical development. Here, we report the discovery and characterization of a second generation clinical MDM2 inhibitor, RG7388, with superior potency and selectivity.

The p53 tumor suppressor is a potent transcription factor that plays a key role in the regulation of cellular responses to stress. It is controlled by its negative regulator MDM2, which binds directly to p53 and inhibits its transcriptional activity. MDM2 also targets p53 for degradation by the proteasome. Many tumors produce high levels of MDM2, thereby impairing p53 function. Restoration of p53 activity by inhibiting the p53-MDM2 interaction may represent a novel approach to cancer treatment. RG7112 (2g) is the first clinical small-molecule MDM2 inhibitor designed to occupy the p53-binding pocket of MDM2. In cancer cells expressing wild-type p53, RG7112 stabilizes p53 and activates the p53 pathway, leading to cell cycle arrest, apoptosis, and inhibition or regression of human tumor xenografts. KEYWORDS: MDM2, p53, RG7112, protein−protein interaction, cancer p53 is a potent tumor suppressor that activates the transcription of a subset of genes controlling cell-cycle progression and apoptosis.1−3 Dysregulation of the p53 pathway, including mutation or deletion of the p53 gene and changes in downstream signaling molecules, is the most frequent alteration in human cancers.4 MDM2 is a negative regulator of p53 that binds the transactivation domain of p53 and inhibits its ability to activate transcription.5−8 MDM2 is also an E3 ubiquitin ligase that targets p53 for proteosomal degradation.9 In a variety of solid tumors and hematologic malignancies, MDM2 overexpression is one of the mechanisms by which the wildtype p53 function is impaired.10 Given the central role of MDM2 in regulating p53 activity and stability, developing small-molecule inhibitors of MDM2 could offer a novel approach to treating cancers. 11,12The crystal structure of a p53-derived peptide bound to the p53 binding domain of MDM2 revealed the existence of a deep hydrophobic clef on the surface of the MDM2 molecule. 13Three amino acid residues from the p53 peptide (Phe19, Trp23, and Leu26) play critical roles in the binding between the two proteins by projecting hydrophobic side-chains deep into the cavity of the MDM2 molecule. These structural features of the p53-MDM2 complex suggested the likelihood of identifying small-molecule inhibitors that can successfully block the interaction between the two proteins. Compounds with the ability to inhibit the binding between p53 and MDM2 have been reported. 14−17 We previously reported the discovery of a series of 4,5-dihydroimidazolines called Nutlins. These compounds, exemplified by compound 1 (Figure 1), were discovered through screening and subsequent medicinal chemistry optimization. 18 Compound 1, also known as Nutlin-3a, has become a tool of choice to study p53 biology and therapeutic applications.19 Although these early lead compounds have shown good cellular activity and provided the mechanistic proof-of-concept for inhibiting p53-MDM2 interaction for cancer therapy, their pharmacological properties were suboptimal for clinical development. Here, we describe

Surface-enhanced Raman scattering (SERS) technique with naturally born analyte identification capability can achieve ultrahigh sensitivity. However, the sensitivity and quantification capability of SERS are assumed to be mutually exclusive. Here, we prohibit the formation of the ultrasensitive SERS sites to achieve a high quantification capability through separating the gold (Au) nanorods from approaching each other with thick metal organic framework (MOF) shells. The sensitivity decrease caused by the absence of the ultrasensitive SERS sites is compensated by the analyte enrichment function of a slippery surface. The porous MOF shell around the Au nanorod only allows analytes smaller than the pore size to approach the Au nanorods and contribute to the SERS spectrum within the complex sample, greatly enhancing the analyte identification capability. Overall, we have demonstrated an integrated SERS platform with analyte enrichment and analyte filtration function, realizing sensitive, quantitative, and size selective analyte identification in complex environments.

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Using the ultrafast pump-probe transient absorption spectroscopy, the femtosecond-resolved plasmon-exciton interaction of graphene-Ag nanowire hybrids is experimentally investigated, in the VIS-NIR region. The plasmonic lifetime of Ag nanowire is about 150 ± 7 femtosecond (fs). For a single layer of graphene, the fast dynamic process at 275 ± 77 fs is due to the excitation of graphene excitons, and the slow process at 1.4 ± 0.3 picosecond (ps) is due to the plasmonic hot electron interaction with phonons of graphene. For the graphene-Ag nanowire hybrids, the time scale of the plasmon-induced hot electron transferring to graphene is 534 ± 108 fs, and the metal plasmon enhanced graphene plasmon is about 3.2 ± 0.8 ps in the VIS region. The graphene-Ag nanowire hybrids can be used for plasmon-driven chemical reactions. This graphene-mediated surface-enhanced Raman scattering substrate significantly increases the probability and efficiency of surface catalytic reactions co-driven by graphene-Ag nanowire hybridization, in comparison with reactions individually driven by monolayer graphene or single Ag nanowire. This implies that the graphene-Ag nanowire hybrids can not only lead to a significant accumulation of high-density hot electrons, but also significantly increase the plasmon-to-electron conversion efficiency, due to strong plasmon-exciton coupling.