Author: Tan, Shyh-Han ; Li, Hua ; Srivastava, Shiv ; Katta, Shilpa ; Xavier, Charles P. ; Srinivasan, Alagarsamy ; McLeod, David G. ; Jamal, Muhammad ; Ravindranath, Lakshmi ; Dobi, Albert ; Srivatsan, Eri S. ; Sreenath, Taduru L. ; Mohamed, Ahmed A. ; Petrovics, Gyorgy ; Huang, Wei ; Srivastava, Meera

AbstractThe oncogenic activation of the ETS-related gene (ERG) due to gene fusions is present in over half of prostate cancers in Western countries. Because of its high incidence and oncogenic role, ERG and components of ERG network have emerged as potential drug targets for prostate cancer. Utilizing gene expression datasets, from matched normal and prostate tumor epithelial cells, an association of NOTCH transcription factors with ERG expression status was identified, confirming that NOTCH factors are direct transcriptional targets of ERG. Inhibition of ERG in TMPRSS2-ERG–positive VCaP cells led to decreased levels of NOTCH1 and 2 proteins and downstream transcriptional targets and partially recapitulated the phenotypes associated with ERG inhibition. Regulation of NOTCH1 and 2 genes by ERG were also noted with ectopic ERG expression in LNCaP (ERG-negative prostate cancer) and RWPE-1 (benign prostate–derived immortalized) cells. Furthermore, inhibition of NOTCH by the small-molecule γ-secretase inhibitor 1, GSI-1, conferred an increased sensitivity to androgen receptor (AR) inhibitors (bicalutamide and enzalutamide) or the androgen biosynthesis inhibitor (abiraterone) in VCaP cells. Combined treatment with bicalutamide and GSI-1 showed strongest inhibition of AR, ERG, NOTCH1, NOTCH2, and PSA protein levels along with decreased cell growth, cell survival, and enhanced apoptosis. Intriguingly, this effect was not observed in ERG-negative prostate cancer cells or immortalized benign/normal prostate epithelial cells. These data underscore the synergy of AR and NOTCH inhibitors in reducing the growth of ERG-positive prostate cancer cells.Implications: Combinational targeting of NOTCH and AR signaling has therapeutic potential in advanced ERG-driven prostate cancers. Mol Cancer Res; 15(10); 1308–17. ©2017 AACR.

01 Dec 2016·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

Design and synthesis of water soluble β-aminosulfone analogues of SCH 900229 as γ-secretase inhibitors

Q4 · MEDICINE

Article

Author: Burnett, Duane A ; Cohen-Williams, Mary E ; Lee, Julie ; Terracina, Giuseppe ; Zhang, Lili ; Zhang, Qi ; Hyde, Lynn A ; Wu, Wen-Lian ; Jiang, Qin ; Song, Lixin ; Greenlee, William J ; Parker, Eric M ; Nomeir, Amin ; Clader, John ; Del Vecchio, Robert A

In this paper we describe our strategy to improve the aqueous solubility of SCH 900229, a potent PS1-selective γ-secretase inhibitor for the treatment of Alzheimer's disease. Incorporation of ionizable amino groups into the side chain terminal generates water soluble β-aminosulfone analogues of SCH 900229 that maintain robust in vitro potency and in vivo efficacy.

01 Nov 2016·Biomeditsinskaya Khimiya

Development of blood-brain barrier under the modulation of HIF activity in astroglial and neuronal cells in vitro

Article

Author: Kuvacheva, N.V. ; Ruzaeva, V.A. ; Boitsova, E.B. ; Morgun, A.V. ; Taranushenko, T.E. ; Salmina, A.B. ; Khilazheva, E.D. ; Martynova, G.P. ; Pozhilenkova, E.A.

Barriergenesis is the process of maturation of the primary vascular network of the brain responsible for the establishment of the blood-brain barrier. It represents a combination of factors that, on the one hand, contribute to the process of migration and tubulogenesis of endothelial cells (angiogenesis), on the other hand, contribute to the formation of new connections between endothelial cells and other elements of the neurovascular unit. Astrocytes play a key role in barriergenesis, however, mechanisms of their action are still poorly examined. We have studied the effects of HIF-1 modulators acting on the cells of non-endothelial origin (neurons and astrocytes) on the development of the blood-brain barrier in vitro. Application of FM19G11 regulating expression of HIF-1 activity and GSI-1 suppressing gamma-secretase and/or proteasomal activity resulted in the elevated expression of thrombospondins and matrix metalloproteinases in the developing blood-brain barrier. However, it caused the opposite effect on VEGF expression thus promoting barrier maturation in vitro.

100 Deals associated with GSI-1

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Indication	Highest Phase	Country/Location	Organization	Date
Breast Cancer	Preclinical	US	Louisiana State University Health Shreveport	01 May 2007
Alzheimer Disease	Preclinical	-	Merck Sharp & Dohme Corp.	-

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