- Cellular Compositions Used To Restore Stem Cell or Progenitor Cell Function and Methods Related Thereto
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This disclosure relates to compounds, compositions and methods of epigenetically transforming cells. In certain embodiments, the disclosure relates to methods of generating epigenetically altered cells comprising mixing isolated cells with compositions di
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- BLOCKING TOLL-LIKE RECEPTOR 9 SIGNALING WITH SMALL MOLECULE ANTAGONIST
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The present invention relates to small molecule4-(piperazin-1-yl)quinazolin-2-amino compounds with formula (I) useful for inhibiting signalling by certain toll-like receptors (TLRs), especially TLR9. Toll-like receptors (TLRs) are members of the larger family of evolutionarily conserved pattern recognition receptors which are critical first line of defence for self-nonself discrimination by the host immune response. Aberrant TLR9 activation is implicated in autoreactive inflammation in different autoimmune diseases. The invention depicts compounds with formula (I), composition and methods can be used in a number of clinical applications, including as pharmaceutical agents and methods for treating conditions involving unwanted immune activity due to TLR9 activation.
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- Histone lysine methyltransferase structure activity relationships that allow for segregation of G9a inhibition and anti-Plasmodium activity
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Plasmodium falciparum HKMTs (PfHKMTs) play a key role in controlling Plasmodium gene expression and represent exciting new anti-malarial epigenetic targets. Using an inhibitor series derived from the diaminoquinazoline HKMT inhibitory chemotype, we have previously identified compounds with highly promising antimalarial activity, including irreversible asexual cycle blood stage-independent cytotoxic activity at nM concentrations, oral efficacy in in vivo models of disease, and the unprecedented ability to reactivate dormant liver stage parasites (hypnozoites). However, future development of this series will need to address host versus parasite selectivity, where inhibitory activity against human G9a is removed from the lead compounds, while maintaining potent anti-Plasmodium activity. Herein, we report an extensive study of the SAR of this series against both G9a and P. falciparum. We have identified key SAR features which demonstrate that high parasite vs. G9a selectivity can be achieved by selecting appropriate substituents at position 2, 4 and 7 of the quinazoline ring. We have also, in turn, discovered that potent G9a inhibitors can be identified by employing a 6-carbon 'Nle mimic' at position 7. Together, this data suggests that while broadly similar, the G9a and potential PfHKMT target(s) binding pockets and/or binding modes of the diaminoquinazoline analogues exhibit clear and exploitable differences. Based on this, we believe this scaffold to have clear potential for development into a novel anti-malarial therapeutic.
- Sundriyal, Sandeep,Chen, Patty B.,Lubin, Alexandra S.,Lueg, Gregor A.,Li, Fengling,White, Andrew J. P.,Malmquist, Nicholas A.,Vedadi, Masoud,Scherf, Artur,Fuchter, Matthew J.
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p. 1069 - 1092
(2017/07/12)
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- Compounds and compositions used to epigenetically transform cells and methods related thereto
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This disclosure relates to compounds, compositions and methods of epigenetically transforming cells. In certain embodiments, the disclosure relates to methods of generating epigenetically altered cells comprising mixing isolated cells with compositions di
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- COMPOUNDS AND COMPOSITIONS USED TO EPIGENETICALLY TRANSFORM CELLS AND METHODS RELATED THERETO
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This disclosure relates to compounds, compositions and methods of epigenetically transforming cells. In certain embodiments, the disclosure relates to methods of generating epigenetically altered cells comprising mixing isolated cells with compositions disclosed herein under conditions such that epigenetically altered cells are formed. In certain embodiments, the disclosure contemplates inducing cells, such as adult somatic cells or cells that are not naturally pluripotent, into cells with chemically induce pluripotency. In certain embodiments, the disclosure contemplates certain compounds disclosed herein, compounds disclosed herein optionally substituted with one or more substituents, derivatives, or salts thereof, for these purposes.
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- Protein lysine methyltransferase g9a inhibitors: Design, synthesis, and structure activity relationships of 2,4-diamino-7-aminoalkoxy-quinazolines.
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Protein lysine methyltransferase G9a, which catalyzes methylation of lysine 9 of histone H3 (H3K9) and lysine 373 (K373) of p53, is overexpressed in human cancers. Genetic knockdown of G9a inhibits cancer cell growth, and the dimethylation of p53 K373 results in the inactivation of p53. Initial SAR exploration of the 2,4-diamino-6,7-dimethoxyquinazoline template represented by 3a (BIX01294), a selective small molecule inhibitor of G9a and GLP, led to the discovery of 10 (UNC0224) as a potent G9a inhibitor with excellent selectivity. A high resolution X-ray crystal structure of the G9a?10 complex, the first cocrystal structure of G9a with a small molecule inhibitor, was obtained. On the basis of the structural insights revealed by this cocrystal structure, optimization of the 7-dimethylaminopropoxy side chain of 10 resulted in the discovery of 29 (UNC0321) (Morrison Ki = 63 pM), which is the first G9a inhibitor with picomolar potency and the most potent G9a inhibitor to date.
- Liu, Feng,Chen, Xin,Allali-Hassani, Abdellah,Quinn, Amy M.,Wigle, Tim J.,Wasney, Gregory A.,Dong, Aiping,Senisterra, Guillermo,Chau, Irene,Siarheyeva, Alena,Norris, Jacqueline L.,Kireev, Dmitri B.,Jadhav, Ajit,Herold, J. Martin,Janzen, William P.,Arrowsmith, Cheryl H.,Frye, Stephen V.,Brown, Peter J.,Simeonov, Anton,Vedadi, Masoud,Jin, Jian
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experimental part
p. 5844 - 5857
(2010/10/03)
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- Discovery of a 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine methyltransferase G9a
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SAR exploration of the 2,4-diamino-6,7-dimethoxyquinazoline template led to the discovery of 8 (UNC0224) as a potent and selective G9a inhibitor. A high resolution X-ray crystal structure of the G9a-8 complex, the first cocrystal structure of G9a with a small molecule inhibitor, was obtained. The cocrystal structure validated our binding hypothesis and will enable structure-based design of novel inhibitors. 8 is a useful tool for investigating the biology of G9a and its roles in chromatin remodeling.
- Liu, Feng,Chen, Xin,Allali-Hassani, Abdellah,Quinn, Amy M.,Wasney, Gregory A.,Dong, Aiping,Barsyte, Dalia,Kozieradzki, Ivona,Senisterra, Guillermo,Chau, Irene,Siarheyeva, Alena,Kireev, Dmitri B.,Jadhav, Ajit,Herold, J. Martin,Frye, Stephen V.,Arrowsmith, Cheryl H.,Brown, Peter J.,Simeonov, Anton,Vedadi, Masoud,Jin, Jian
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supporting information; experimental part
p. 7950 - 7953
(2010/08/13)
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- Quinazolines: Combined type 3 and 4 phosphodiesterase inhibitors
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A series of quinazolines has been prepared and evaluated for its ability to inhibit cyclic AMP phosphodiesterase type 3, type 4A, 4B and 4D. The most potent inhibitors showed IC50 values in the nanomolar range for type 3 and type 4 isoforms and bind with high affinity to the [3H]rolipram binding site. These quinazolines represent a new family of potent mixed PDE 3 / 4 inhibitors and are expected to have a therapeutic potential.
- Charpiot, Brigitte,Brun, Jvan,Donze, Irene,Naef, Reto,Stefani, Monique,Mueller, Thomas
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p. 2891 - 2896
(2007/10/03)
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- Tetrazolo[A]quinazol-5-ones antiallergy and antiulcer agents
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A series of tetrazolo[a]quinazol-5-ones, methods for their production and use as antiallergy agents and antiulcer agents.
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- Synthesis and identification of the major metabolites of prazosin formed in dog and rat
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The 6 O demethyl and 7 O demethyl analogues of the new antihypertensive drug prazosin [2 [4 (2 furoyl) piperazin 1 yl] 4 amino 6,7 dimethoxyquinazoline hydrochloride] have been unequivocally synthesized via separate ten step reaction sequences starting from isovanillin and vanillin, respectively. The 6 O demethyl derivative was found to be identical with the major prazosin metabolite formed in dog and rat, while the 7 O demethyl derivative was identical with another, less prevalent but significant metabolite. Two minor metabolites of prazosin, 2 (1 piperazinyl) 4 amino 6,7 dimethoxyquinazoline and 2,4 diamino 6,7 dimethoxyquinazoline, are also described. All four metabolites are less potent blood pressure lowering agents in dogs than prazosin but may contribute to its antihypertensive effect, since they account for a major portion of the administered dose.
- Althuis,Hess
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p. 146 - 149
(2007/10/05)
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