42456-40-6Relevant articles and documents
Synthesis, Identification, and Structure-Activity Relationship Analysis of GATA4 and NKX2-5 Protein-Protein Interaction Modulators
Jumppanen, Mikael,Kinnunen, Sini M.,V?lim?ki, Mika J.,Talman, Virpi,Auno, Samuli,Bruun, Tanja,Boije Af Genn?s, Gustav,Xhaard, Henri,Aumüller, Ingo B.,Ruskoaho, Heikki,Yli-Kauhaluoma, Jari
, p. 8284 - 8310 (2019/10/11)
Transcription factors GATA4 and NKX2-5 directly interact and synergistically activate several cardiac genes and stretch-induced cardiomyocyte hypertrophy. Previously, we identified phenylisoxazole carboxamide 1 as a hit compound, which inhibited the GATA4-NKX2-5 transcriptional synergy. Here, the chemical space around the molecular structure of 1 was explored by synthesizing and characterizing 220 derivatives and structurally related compounds. In addition to the synergistic transcriptional activation, selected compounds were evaluated for their effects on transcriptional activities of GATA4 and NKX2-5 individually as well as potential cytotoxicity. The structure-activity relationship (SAR) analysis revealed that the aromatic isoxazole substituent in the southern part regulates the inhibition of GATA4-NKX2-5 transcriptional synergy. Moreover, inhibition of GATA4 transcriptional activity correlated with the reduced cell viability. In summary, comprehensive SAR analysis accompanied by data analysis successfully identified potent and selective inhibitors of GATA4-NKX2-5 transcriptional synergy and revealed structural features important for it.
Development of Glucose Regulated Protein 94-Selective Inhibitors Based on the BnIm and Radamide Scaffold
Crowley, Vincent M.,Khandelwal, Anuj,Mishra, Sanket,Stothert, Andrew R.,Huard, Dustin J. E.,Zhao, Jinbo,Muth, Aaron,Duerfeldt, Adam S.,Kizziah, James L.,Lieberman, Raquel L.,Dickey, Chad A.,Blagg, Brian S. J.
, p. 3471 - 3488 (2016/05/19)
Glucose regulated protein 94 (Grp94) is the endoplasmic reticulum resident of the heat shock protein 90 kDa (Hsp90) family of molecular chaperones. Grp94 associates with many proteins involved in cell adhesion and signaling, including integrins, Toll-like receptors, immunoglobulins, and mutant myocilin. Grp94 has been implicated as a target for several therapeutic areas including glaucoma, cancer metastasis, and multiple myeloma. While 85% identical to other Hsp90 isoforms, the N-terminal ATP-binding site of Grp94 possesses a unique hydrophobic pocket that was used to design isoform-selective inhibitors. Incorporation of a cis-amide bioisostere into the radamide scaffold led to development of the original Grp94-selective inhibitor, BnIm. Structure-activity relationship studies have now been performed on the aryl side chain of BnIm, which resulted in improved analogues that exhibit better potency and selectivity for Grp94. These analogues also manifest superior antimigratory activity in a metastasis model as well as enhanced mutant myocilin degradation in a glaucoma model compared to BnIm.
N6-SUBSTITUTED ADENOSINE DERIVATIVES AND N6-SUBSTITUTED ADENINE DERIVATIVES AND USES THEREOF
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Paragraph 0149, (2013/03/26)
The present invention provides N6-substituted adenosine derivatives and N6-substituted adenine derivatives, manufacturing methods thereof, a pharmaceutical composition comprising the said compounds above, and uses of these compounds in manufacturing medicaments and health-care products for treating insomnia, convulsion, epilepsy, and Parkinson's diseases, and preventing and treating dementia.