SUMMARY Age-related human hematopoietic stem cell (HSC) exhaustion and myeloid-lineage skewing promote oncogenic transformation of hematopoietic progenitor cells into therapy-resistant leukemia stem cells (LSC) in secondary acute myeloid leukemia (sAML). While acquisition of clonal DNA mutations have been linked to increased rates of sAML for individuals over 60, the contribution of RNA processing alterations to human hematopoietic stem and progenitor aging and LSC generation remains unclear. Comprehensive RNA-sequencing and splice isoform-specific PCR uncovered characteristic RNA splice isoform expression patterns that distinguished normal young and aged HSPCs, compared with malignant MDS and AML progenitors. In splicing reporter assays and in pre-clinical patient-derived AML models, treatment with a pharmacologic splicing modulator, 17S-FD-895, reversed pro-survival splice isoform switching and significantly impaired LSC maintenance. By comparing splice isoform biomarkers of normal HSPC aging with those of LSC generation, splicing modulation may be employed safely and effectively to prevent relapse – the leading cause of leukemia-related mortality.

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We have synthesized a series of diphenylamine-substituted coumarin, (dicyanomethylene)pyran, and benzophenoxazone dyes and report on their optical and electroluminescent properties, thermal and photooxidative stabilities, and potential as red and green dopants for organic light-emitting diode (OLED) displays or down-conversion fluorescent dyes for external color-converters. Incorporation of the bulky phenyl groups in these dyes delays the onset of concentration quenching when they are dissolved in polymer films. Their improved photoluminescent efficiency and photooxidative stability make them excellent candidates for external color-conversion. The improved electroluminescence and power efficiencies and enhanced thermal stability of 3-(2‘-benzimidazolyl)-7-(diphenylamino)-2H-1-benzopyran-2-one (C7S) as well as its Commission Internationale d'Eclairage (CIE) coordinates suggests its use as a green dopant in OLED devices.

The total synthesis of FD–895 was completed through a strategy that featured the use of a tandem esterification ring–closing metathesis (RCM) process to construct the 12–membered macrolide and a modified Stille coupling to append the side chain. These studies combined with detailed analysis of all four possible C16–C17 stereoisomers, was used to confirm the structure of FD–895 and identify an analog with an enhanced sub-nanomolar bioactivity.

The dysregulation of RNA splicing is a molecular hallmark of disease, including different and often complex cancers. While gaining recognition as a target for therapeutic discovery, understanding the complex mechanisms guiding RNA splicing remains a challenge for chemical biology. The discovery of small molecule splicing modulators has recently enabled an evaluation of the mechanisms of aberrant splicing. We now report on three unique features within the selectivity of splicing modulators. First, we provide evidence that structural modifications within a splicing modulator can alter the splicing of introns in specific genes differently. These studies indicate that structure activity relationships not only have an effect on splicing activity but also include specificity for specific introns within different genes. Second, we find that these splicing modulators also target the mRNAs encoding components of the spliceosome itself. Remarkably, this effect includes the genes for the SF3B complex, a target of pladienolide B and related splicing modulators. Finally, we report on the first observation of a temporal phenomenon associated with small molecule splicing modulation. Combined, these three observations provide an important new perspective for the exploration of splicing modulation in terms of both future medicinal chemistry programs as well as understanding the key facets underlying its timing.