- In Vitro and Cellular Probes to Study PARP Enzyme Target Engagement
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Poly(ADP-ribose) polymerase (PARP) enzymes use nicotinamide adenine dinucleotide (NAD+) to modify up to seven different amino acids with a single mono(ADP-ribose) unit (MARylation deposited by PARP monoenzymes) or branched poly(ADP-ribose) polymers (PARylation deposited by PARP polyenzymes). To enable the development of tool compounds for PARP monoenzymes and polyenzymes, we have developed active site probes for use in in vitro and cellular biophysical assays to characterize active site-directed inhibitors that compete for NAD+ binding. These assays are agnostic of the protein substrate for each PARP, overcoming a general lack of knowledge around the substrates for these enzymes. The in vitro assays use less enzyme than previously described activity assays, enabling discrimination of inhibitor potencies in the single-digit nanomolar range, and the cell-based assays can differentiate compounds with sub-nanomolar potencies and measure inhibitor residence time in live cells. Wigle et al. describe a versatile set of NAD+-competitive probes for PARP enzymes that are used to build high-throughput in vitro and cellular biophysical assays that enable inhibitor screening and determination of residence time.
- Blackwell, Danielle J.,Church, W. David,Desai, Hetvi J.,Keilhack, Heike,Kuntz, Kevin W.,Lu, Alvin Z.,Majer, Christina R.,Niepel, Mario,Perl, Nicholas R.,Ren, Yue,Santospago, Andrew G.,Schenkel, Laurie B.,Swinger, Kerren K.,Vasbinder, Melissa M.,Wigle, Tim J.
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- HETEROARYL COMPOUNDS
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Provided herein are compounds and pharmaceutical compositions comprising said compounds that are useful for treating cancers. Specific cancers include those that are mediated by YAP/TAZ or those that are modulated by the interaction between YAP/TAZ and TEAD.
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Paragraph 00236
(2021/05/29)
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- Preparation method 3 - (tert-butyloxycarbonylamino) propionic acid
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The preparation method of 3 - (t-butoxycarbonylamino) propionic acid comprises the following steps: Step S1, reacting methylaminopropanol with Boc anhydride to generate 3 - (t-butoxycarbonylamino) propanol. Step S2: The 3 - (t-butoxycarbonyl) propanol is subjected to an oxidation reaction under the action of a catalyst to generate the 3 - (t-butoxycarbonylamino) propionic acid. To the preparation method disclosed by the embodiment of the invention, the steps are simple, and the reaction is easy to process. Can be suitable for a pot method, can effectively reduce the waste water that is difficult to handle. The method is more suitable for industrial production.
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Paragraph 0047; 0054; 0057-0061; 0064-0067
(2021/11/19)
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- FLUOROMETHYL-SUBSTITUTED PYRROLE CARBOXAMIDES
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The invention relates to pyrrole carboxamides bearing a fluoromethyl-moiety as voltage gated calcium channel blockers, to pharmaceutical compositions containing these compounds and also to these compounds for use in the treatment and/or prophylaxis of pain and further diseases and/or disorders.
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Paragraph 0779
(2014/03/25)
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- FLUOROMETHYL-SUBSTITUTED PYRROLE CARBOXAMIDES
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The invention relates to pyrrole carboxamides bearing a fluoromethyl- moiety as voltage gated calcium channel blockers, to pharmaceutical compositions containing these compounds and also to these compounds for use in the treatment and/or prophylaxis of pain and further diseases and/or disorders.
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Page/Page column 157
(2014/03/25)
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- Constructions of tetrahydro-γ-carboline skeletons via intramolecular oxidative carbon-carbon bond formation of enamines
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The synthetically and biologically important 4-methyl and 4-methoxy tetrahydro-γ-carboline compounds were readily synthesized in high yields from an aryl amine and a 5-amino-3-oxopentanoate derivative through a series of reactions of enamination, oxidative annulation, deprotection/lactamization and the final reduction reaction of the carbonyl group. The underpinning strategy involves the oxidative C(sp2)-C(sp2) bond formation realized by either Pd(OAc)2/Cu(OAc)2 or a hypervalent iodine reagent.
- Lv, Jinglei,Li, Ji,Zhang-Negrerie, Daisy,Shang, Siyun,Gao, Qingzhi,Du, Yunfei,Zhao, Kang
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supporting information
p. 1929 - 1932
(2013/06/04)
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- Adenine receptor ligands
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The invention relates to adenine receptor ligands useful for treating, alleviating and/or preventing diseases and disorders related to adenine receptor function as well as pharmaceutical compositions comprising such compounds and methods for preparing such compounds. The invention is further directed to the use of these compounds, alone or in combination with other therapeutic agents, for the alleviating, preventing and/or treating diseases and disorders, especially the use as antinociceptive or neuroprotective drugs.
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Page/Page column 15-16
(2010/01/29)
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- RENIN INHIBITORS
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The present invention is directed to aspartic protease inhibitors. The present invention is also directed to pharmaceutical compositions comprising the disclosed aspartic protease inhibitors. The present invention is further directed to methods of antagonizing one or more aspartic proteases in a subject in need thereof, and methods for treating an aspartic protease mediated disorder in a subject using the disclosed aspartic protease inhibitors.
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Page/Page column 73
(2009/01/23)
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- RENIN INHIBITORS
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The present invention is directed to aspartic protease inhibitors. The present invention is also directed to pharmaceutical compositions comprising the disclosed aspartic protease inhibitors. The present invention is further directed to methods of antagon
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Page/Page column 95-96
(2009/01/23)
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- QUINAZOLINE DERIVATIVES
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A quinazoline derivative of the formula (I) wherein: R1, R2, R3, R3a, R4, R5, R5a R6, R7, a, m and p are as defined in the description. Also claimed are pharmaceutical compositions containing the quinazoline derivative, the use of the quinazoline derivatives as medicaments and processes for the preparation of the quinazoline derivative. The quinazoline derivatives of formula (I), are useful in the treatment of hyperproliferative disorders such as a cancer.
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Page/Page column 151
(2008/06/13)
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- ANTIVIRAL AGENT
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The present invention provides an integrase inhibitor. The inventors have have found the following compound of formula (I) possessing an integrase inhibitory activity. (wherein, R C and R D taken together with the neighboring carbon atoms form a ring which may be a condensed ring, Y is hydroxy, mercapto or amino; Z is O, S or NH ; R A is a group shown by (wherein, C ring is N-containing aromatic heterocycle) or the like)
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- HUMAN LEUKOCYTE ELASTASE (HLE) INHIBITORS, AND RELATED PHARMACEUTICAL COMPOSITIONS AND METHODS OF USE
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Novel therapeutic agents useful as inhibitors of HLE are provided. The compounds have the structural formula (I) STR1 wherein R 1 through R 9, m, n and p are as defined herein. Methods of using the compounds of formula (I) to inhibit serine proteases and
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- Novel Asp32-replacement tetrapeptide analogues as potent and selective CCK-A agonists
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A series of novel CCK tetrapeptide analogues of the general formula Boc- Trp-Lys(Tac)-N(R)-(CH2)(n)CON(R')Phe-NH2 (Tac = o-tolylaminocarbonyl), where R,R' = H or Me and n = 1-5, have been synthesized and tested. These analogues, which lack an acidic residue at the penultimate position, demonstrated surprisingly high CCK-A receptor affinity and selectivity. The effect of N-methylation pattern on CCK-A receptor affinity showed consistent trends for analogues in which n = 1, 2, or 3, with the di-N-methylated analogues having the highest affinity in each case. However, none of these analogues had full agonist activity, as measured by percent maximal PI hydrolysis. Two conformationally constrained analogues also demonstrated high CCK-A receptor affinity and selectivity, as well as nearly maximal agonist activity. In addition, one of these conformationally-constrained analogues demonstrated anorectic activity in rats.
- Elliott,Kopecka,Tufano,Shue,Gauri,Lin -,Bianchi,Miller,Witte,Stashko,Asin,Nikkel,Bednarz,Nadzan
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p. 1562 - 1568
(2007/10/02)
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