Parallel Synthesis and Biological Evaluation of 837 Analogues of Procaspase-Activating Compound 1 (PAC-1)

Procaspase-Activating Compound 1 (<b>PAC-1</b>) is an <i>ortho</i>-hydroxy <i>N</i>-acyl hydrazone that enhances the enzymatic activity of procaspase-3 in vitro and induces apoptosis in cancer cells. An analogue of <b>PAC-1</b>, called <b>S-PAC-1</b>, was evaluated in a veterinary clinical trial in pet dogs with lymphoma and found to have considerable potential as an anticancer agent. With the goal of identifying more potent compounds in this promising class of experimental therapeutics, a combinatorial library based on <b>PAC-1</b> was created, and the compounds were evaluated for their ability to induce death of cancer cells in culture. For library construction, 31 hydrazides were condensed in parallel with 27 aldehydes to create 837 <b>PAC-1</b> analogues, with an average purity of 91%. The compounds were evaluated for their ability to induce apoptosis in cancer cells, and through this work, six compounds were discovered to be substantially more potent than <b>PAC-1</b> and <b>S-PAC-1</b>. These six hits were further evaluated for their ability to relieve zinc-mediated inhibition of procaspase-3 in vitro. In general, the newly identified hit compounds are two- to four-fold more potent than <b>PAC-1</b> and <b>S-PAC-1</b> in cell culture, and thus have promise as experimental therapeutics for treatment of the many cancers that have elevated expression levels of procaspase-3

Parallel Synthesis and Biological Evaluation of 837 Analogues of Procaspase-Activating Compound 1 (PAC-1)

Procaspase-Activating Compound 1 (<b>PAC-1</b>) is an <i>ortho</i>-hydroxy <i>N</i>-acyl hydrazone that enhances the enzymatic activity of procaspase-3 in vitro and induces apoptosis in cancer cells. An analogue of <b>PAC-1</b>, called <b>S-PAC-1</b>, was evaluated in a veterinary clinical trial in pet dogs with lymphoma and found to have considerable potential as an anticancer agent. With the goal of identifying more potent compounds in this promising class of experimental therapeutics, a combinatorial library based on <b>PAC-1</b> was created, and the compounds were evaluated for their ability to induce death of cancer cells in culture. For library construction, 31 hydrazides were condensed in parallel with 27 aldehydes to create 837 <b>PAC-1</b> analogues, with an average purity of 91%. The compounds were evaluated for their ability to induce apoptosis in cancer cells, and through this work, six compounds were discovered to be substantially more potent than <b>PAC-1</b> and <b>S-PAC-1</b>. These six hits were further evaluated for their ability to relieve zinc-mediated inhibition of procaspase-3 in vitro. In general, the newly identified hit compounds are two- to four-fold more potent than <b>PAC-1</b> and <b>S-PAC-1</b> in cell culture, and thus have promise as experimental therapeutics for treatment of the many cancers that have elevated expression levels of procaspase-3

Malaria-Infected Mice Are Cured by a Single Oral Dose of New Dimeric Trioxane Sulfones Which Are Also Selectively and Powerfully Cytotoxic to Cancer Cells

A new series of 6 dimeric trioxane sulfones has been prepared from the natural trioxane artemisinin in five or six chemical steps. One of these thermally and hydrolytically stable new chemical entities (4c) completely cured malaria-infected mice via a single oral dose of 144 mg/kg. At a much lower single oral dose of only 54 mg/kg combined with 13 mg/kg of mefloquine hydrochloride, this trioxane dimer 4c as well as its parent trioxane dimer 4b also completely cured malaria-infected mice. Both dimers 4c and 4b were potently and selectively cytotoxic toward five cancer cell lines

Supplementary Information from GR and ER Coactivation Alters the Expression of Differentiation Genes and Associates with Improved ER⁺ Breast Cancer Outcome

Supplementary Information: Supplementary Materials and Methods, Supplementary Methods, Supplementary Figure Legends, and Description of Supplementary Data Files</p

Supplementary Data File 2 from GR and ER Coactivation Alters the Expression of Differentiation Genes and Associates with Improved ER⁺ Breast Cancer Outcome

Analyzed gene expression data for GR- and ER-bound genes</p

Supplementary Data File 1 from GR and ER Coactivation Alters the Expression of Differentiation Genes and Associates with Improved ER⁺ Breast Cancer Outcome

Analyzed gene expression data for GR-bound genes</p

Supplementary Figures 1-5 from GR and ER Coactivation Alters the Expression of Differentiation Genes and Associates with Improved ER⁺ Breast Cancer Outcome

Supplementary Figure 1. ChIP-seq for GR and ER peaks and associated genes and motifs. Supplementary Figure 2. GR immunoprecipitation demonstrates ER interaction. Supplementary Figure 3. Most represented transcription factor response element motifs in Dex/E2-treated EBR and GBR peaks in regulatory regions of KDM4B, IGFBP4, and VDR. Supplementary Figure 4. Knockdown efficiency at 24h and 48h as measured by Q-RT-PCR, normalized to control siRNA pool. Supplementary Figure 5. Flow chart of GR ChIP-seq data analysis and integration of genome-wide gene expression (microarray) data.</p

Supplemental Tables from Selective Glucocorticoid Receptor Modulators (SGRMs) Delay Castrate-Resistant Prostate Cancer Growth

Supplemental Tables 1-2</p

Supplemental Figures from Selective Glucocorticoid Receptor Modulators (SGRMs) Delay Castrate-Resistant Prostate Cancer Growth

Supplemental Figures 1-8</p

Supplementary File 1 from Discovery of a Glucocorticoid Receptor (GR) Activity Signature Using Selective GR Antagonism in ER-Negative Breast Cancer

Patient and tumor prognostic values of study cohorts and a flow chart of the study design.</p