Supplementary Tables 1-2 from Development of a Novel Multi-Isoform ALDH Inhibitor Effective as an Antimelanoma Agent

Supplementary table 1: RT-PCR analysis of the expression of ALDH isoforms in melanoma cell lines and isolated ALDH+ and ALDH- cells. Supplementary table 2: KS100 has no human off-target effects based on the Erebus algorithm.</p

Supplementary Figures 1-7 from Development of a Novel Multi-Isoform ALDH Inhibitor Effective as an Antimelanoma Agent

Supplementary Figure 1: KS100 is a multi-ALDH inhibitor. Supplementary Figure 2: Conformational arrangements of ALDH1A1, 2, and 3A1 are structurally identical. Supplementary Figure 3: Representative dot plots of Aldered staining of UACC 903 cells following ALDH inhibitor treatment. Supplementary Figure 4: Representative dot plots of Aldered staining of 1205 Lu cells following ALDH inhibitor treatment. Supplementary Figure 5: KS100 reduces enzymatic ALDH activity in cell lysates. Supplementary Figure 6: Representative dot plots of Annexin-V-PE/7-AAD staining of UACC 903 cells following ALDH inhibitor treatment. Supplementary Figure 7: Representative dot plots of Annexin-V-PE/7-AAD staining of 1205 Lu cells following ALDH inhibitor treatment.</p

Supplementary Data from ASR490, a Small Molecule, Overrides Aberrant Expression of <i>Notch1</i> in Colorectal Cancer

Supplementary Files</p

DataSheet1_Urolithin A analog inhibits castration-resistant prostate cancer by targeting the androgen receptor and its variant, androgen receptor-variant 7.PDF

We investigated the efficacy of a small molecule ASR-600, an analog of Urolithin A (Uro A), on blocking androgen receptor (AR) and its splice variant AR-variant 7 (AR-V7) signaling in castration-resistant prostate cancer (CRPC). ASR-600 effectively suppressed the growth of AR+ CRPC cells by inhibiting AR and AR-V7 expressions; no effect was seen in AR− CRPC and normal prostate epithelial cells. Biomolecular interaction assays revealed ASR-600 binds to the N-terminal domain of AR, which was further confirmed by immunoblot and subcellular localization studies. Molecular studies suggested that ASR-600 promotes the ubiquitination of AR and AR-V7 resulting in the inhibition of AR signaling. Microsomal and plasma stability studies suggest that ASR-600 is stable, and its oral administration inhibits tumor growth in CRPC xenografted castrated and non-castrated mice. In conclusion, our data suggest that ASR-600 enhances AR ubiquitination in both AR+ and AR-V7 CRPC cells and inhibits their growth in vitro and in vivo models.</p

DataSheet2_Urolithin A analog inhibits castration-resistant prostate cancer by targeting the androgen receptor and its variant, androgen receptor-variant 7.PDF

We investigated the efficacy of a small molecule ASR-600, an analog of Urolithin A (Uro A), on blocking androgen receptor (AR) and its splice variant AR-variant 7 (AR-V7) signaling in castration-resistant prostate cancer (CRPC). ASR-600 effectively suppressed the growth of AR+ CRPC cells by inhibiting AR and AR-V7 expressions; no effect was seen in AR− CRPC and normal prostate epithelial cells. Biomolecular interaction assays revealed ASR-600 binds to the N-terminal domain of AR, which was further confirmed by immunoblot and subcellular localization studies. Molecular studies suggested that ASR-600 promotes the ubiquitination of AR and AR-V7 resulting in the inhibition of AR signaling. Microsomal and plasma stability studies suggest that ASR-600 is stable, and its oral administration inhibits tumor growth in CRPC xenografted castrated and non-castrated mice. In conclusion, our data suggest that ASR-600 enhances AR ubiquitination in both AR+ and AR-V7 CRPC cells and inhibits their growth in vitro and in vivo models.</p

DataSheet3_Urolithin A analog inhibits castration-resistant prostate cancer by targeting the androgen receptor and its variant, androgen receptor-variant 7.PDF

We investigated the efficacy of a small molecule ASR-600, an analog of Urolithin A (Uro A), on blocking androgen receptor (AR) and its splice variant AR-variant 7 (AR-V7) signaling in castration-resistant prostate cancer (CRPC). ASR-600 effectively suppressed the growth of AR+ CRPC cells by inhibiting AR and AR-V7 expressions; no effect was seen in AR− CRPC and normal prostate epithelial cells. Biomolecular interaction assays revealed ASR-600 binds to the N-terminal domain of AR, which was further confirmed by immunoblot and subcellular localization studies. Molecular studies suggested that ASR-600 promotes the ubiquitination of AR and AR-V7 resulting in the inhibition of AR signaling. Microsomal and plasma stability studies suggest that ASR-600 is stable, and its oral administration inhibits tumor growth in CRPC xenografted castrated and non-castrated mice. In conclusion, our data suggest that ASR-600 enhances AR ubiquitination in both AR+ and AR-V7 CRPC cells and inhibits their growth in vitro and in vivo models.</p

Supplementary Figures 1-8 from Modifications to the Framework Regions Eliminate Chimeric Antigen Receptor Tonic Signaling

Supplementary Figures and Legends</p

Functional Gly297Ser Variant of the Physiological Dysglycemic Peptide Pancreastatin is a Novel Risk Factor for Cardiometabolic Disorders

Pancreastatin (PST), a chromogranin A (CHGA)-derived potent physiological dysglycemic peptide, regulates glucose/insulin homeostasis. We have identified a non-synonymous functional PST variant (p.Gly297Ser; rs9658664) that occurs in a large section of human populations. Association analysis of this single nucleotide polymorphism with cardiovascular/metabolic diseases states in Indian populations (n≈4300 subjects) displays elevated plasma glucose, glycosylated hemoglobin, diastolic blood pressure and catecholamines in Gly/Ser subjects as compared to wild-type individuals (Gly/Gly). Consistently, the 297Ser allele confers an increased risk (~1.3-1.6-fold) for type-2 diabetes/hypertension/coronary artery disease/metabolic syndrome. In corroboration, the variant peptide (PST-297S) displays gain-of-potency in several cellular events relevant for cardiometabolic disorders (e.g., increased expression of gluconeogenic genes, increased catecholamine secretion, greater inhibition of insulin-stimulated glucose-uptake) than the wild-type peptide (PST-WT). Computational docking analysis and molecular dynamics simulations show higher affinity binding of PST-297S peptide with glucose-regulated protein 78 (GRP78) and insulin receptor (IR) than PST-WT, providing a mechanistic basis for the enhanced activity of the variant peptide. In vitro binding assays validate these in silico predictions of PST peptides binding to GRP78 and IR. In conclusion, the PST 297Ser allele influences cardiovascular/metabolic phenotypes and emerges as a novel risk factor for type-2 diabetes/hypertension/coronary artery disease in human populations