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Malignant rhabdoid tumors (MRTs) are aggressive pediatric cancers arising in brain, kidney and soft tissues, which are characterized by loss of the tumor suppressor SNF5/SMARCB1. MRTs are poorly responsive to chemotherapy and thus a high unmet clinical need exists for novel therapies for MRT patients. SNF5 is a core subunit of the SWI/SNF chromatin remodeling complex which affects gene expression by nucleosome remodeling. Here, we report that loss of SNF5 function correlates with increased expression of fibroblast growth factor receptors (FGFRs) in MRT cell lines and primary tumors and that re-expression of SNF5 in MRT cells causes a marked repression of FGFR expression. Conversely, siRNA-mediated impairment of SWI/SNF function leads to elevated levels of FGFR2 in human fibroblasts. In vivo, treatment with NVP-BGJ398, a selective FGFR inhibitor, blocks progression of a murine MRT model. Hence, we identify FGFR signaling as an aberrantly activated oncogenic pathway in MRTs and propose pharmacological inhibition of FGFRs as a potential novel clinical therapy for MRTs.

Although most acute skin wounds heal rapidly, non-healing skin ulcers represent an increasing and substantial unmet medical need that urgently requires effective therapeutics. Keratinocytes resurface wounds to re-establish the epidermal barrier by transitioning to an activated, migratory state, but this ability is lost in dysfunctional chronic wounds. Small-molecule regulators of keratinocyte plasticity with the potential to reverse keratinocyte malfunction in situ could offer a novel therapeutic approach in skin wound healing. Utilizing high-throughput phenotypic screening of primary keratinocytes, we identify such small molecules, including bromodomain and extra-terminal domain (BET) protein family inhibitors (BETi). BETi induce a sustained activated, migratory state in keratinocytes in vitro, increase activation markers in human epidermis ex vivo and enhance skin wound healing in vivo. Our findings suggest potential clinical utility of BETi in promoting keratinocyte re-epithelialization of skin wounds. Importantly, this novel property of BETi is exclusively observed after transient low-dose exposure, revealing new potential for this compound class. A chemical screen identified BET bromodomain inhibitors as promoters of keratinocyte regenerative function and skin wound healing. Specifically, low-dose transient treatment with BET inhibitors imposes an activated, migratory state in keratinocytes.

Chemical transformation of nitroso acetals derived from tandem [4 + 2]/[3 + 2] cycloadditions of nitroalkenes have been investigated. New reduction methods were surveyed in an attempt to supplant the use of hydrogen and Raney nickel. Homogeneous catalytic hydrogenation was not successful, but samarium diiodide did effectively and selectively cleave one of the N—O bonds in a number of nitroso acetals. Acid-promoted hydrolysis of the nitroso acetals produced both -alkoxy nitrones and hydroxamic acids selectively via expected pathways.Key words: nitroso acetals, hydroxamic acids, -alkoxy nitrones, reduction, hydrolysis.

Chemical transformation of nitroso acetals derived from tandem [4 + 2]/[3 + 2] cycloadditions of nitroalkenes have been investigated. New reduction methods were surveyed in an attempt to supplant the use of hydrogen and Raney nickel. Homogeneous catalytic hydrogenation was not successful, but samarium diiodide did effectively and selectively cleave one of the N - O bonds in a number of nitroso acetals. Acid-promoted hydrolysis of the nitroso acetals produced both a-alkoxy nitrones and hydroxamic acids selectively via expected pathways.Original Abstract: On a etudie les reactions de transformation chimique des acetals nitroses obtenus par les cycloadditions en tandem [4 + 2]/[3 + 2] de nitroalcenes. On a evalue de nouvelles methodes de reduction qui pourraient eventuellement supplanter lutilisation de lhydrogene et du nickel de Raney. Lhydrogenation catalytique homogene a ete essayee sans succes; toutefois, le diiodure de samarium permet de cliver de facaon efficace et selective lune des liaisons N - O dans un grand nombre dacetals nitroses. Lhydrolyse acidocatalysee des acetals nitroses conduit a la formation selective da- alkoxynitrones ainsi que dacides hydroxamiques par le biais des voies prevues.

The effect of increased structural rigidity on the enantioselectivity shown by a series of naproxen-related selectors when chromatographed on a chiral stationary phase (CSP) has been investigated through the chromatographic evaluation of a series of naproxen analogs. Using the notion of reciprocity, a CSP derived from an optimized conformationally restricted selector was prepared and examined. The performance of this CSP for the enantiomeric separation of acyclic π-acidic analytes is usually inferior to that of the CSP derived from the diallyl amide of naproxen. However, the new CSP displays remarkable specificity for such conformationally restricted analytes as the dinitrobenzamide derivatives of β-lactams. A series of racemic piperidinediones, precursors of biologically active piperidines, have been synthesized from the corresponding α,β-unsaturated esters and N-substituted malonamates. The enantiorners of these cyclic imides were then separated on a chiral stationary phase (CSP). The structures of the analytes were varied for a structure-activity relationship study which aids in formulating a mechanistic rationale to account for the enantiodiscrimination shown by the CSP. A preliminary study the use of an 'optimized' piperidinedione as a selector for a CSP is described. The results of a preliminary study directed towards the synthesis and chromatographic evaluation of a number of (β-aminoalkyl)phosphonates are reported.