- Development of LM98, a Small-Molecule TEAD Inhibitor Derived from Flufenamic Acid
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The YAP-TEAD transcriptional complex is responsible for the expression of genes that regulate cancer cell growth and proliferation. Dysregulation of the Hippo pathway due to overexpression of TEAD has been reported in a wide range of cancers. Inhibition of TEAD represses the expression of associated genes, demonstrating the value of this transcription factor for the development of novel anti-cancer therapies. We report herein the design, synthesis and biological evaluation of LM98, a flufenamic acid analogue. LM98 shows strong affinity to TEAD, inhibits its autopalmitoylation and reduces the YAP-TEAD transcriptional activity. Binding of LM98 to TEAD was supported by 19F-NMR studies while co-crystallization experiments confirmed that LM98 is anchored within the palmitic acid pocket of TEAD. LM98 reduces the expression of CTGF and Cyr61, inhibits MDA-MB-231 breast cancer cell migration and arrests cell cycling in the S phase during cell division.
- Mélin, Léa,Abdullayev, Shuay,Fnaiche, Ahmed,Vu, Victoria,González Suárez, Narjara,Zeng, Hong,Szewczyk, Magdalena M.,Li, Fengling,Senisterra, Guillermo,Allali-Hassani, Abdellah,Chau, Irene,Dong, Aiping,Woo, Simon,Annabi, Borhane,Halabelian, Levon,LaPlante, Steven R.,Vedadi, Masoud,Barsyte-Lovejoy, Dalia,Santhakumar, Vijayaratnam,Gagnon, Alexandre
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p. 2982 - 3002
(2021/08/03)
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- BENZOFLUORENE COMPOUND, MATERIAL FOR LUMIOUS LAYER USING THE COMPOUND, ORGANIC ELECTROLUMINESCENCE ELEMENT, DISPLAY DEVICE AND ILLUMINATING DEVICE
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The invention provides a benzofluorene compound such as one that is applied to an organic electroluminescence element for brining out excellent properties of the organic electroluminescence element. As a material for a luminous layer of the organic electr
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Page/Page column 118
(2017/08/02)
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- INHIBITORS OF THE MENIN-MLL INTERACTION
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The present invention is directed to inhibitors of the interaction of menin with MLL and MLL fusion proteins, pharmaceutical compositions containing the same, and their use in the treatment of cancer and other diseases mediated by the menin-MLL interaction.
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Page/Page column 187
(2018/01/17)
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- Synthesis and structure-activity studies of the V-ATPase inhibitor saliphenylhalamide (SaliPhe) and simplified analogs
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An efficient total synthesis of the potent V-ATPase inhibitor saliphenylhalamide (SaliPhe), a synthetic variant of the natural product salicylihalamide A (SaliA), has been accomplished aimed at facilitating the development of SaliPhe as an anticancer and antiviral agent. This new approach enabled facile access to derivatives for structure-activity relationship studies, leading to simplified analogs that maintain SaliPhe's biological properties. These studies will provide a solid foundation for the continued evaluation of SaliPhe and analogs as potential anticancer and antiviral agents.
- Garcia-Rodriguez, Jose,Mendiratta, Saurabh,White, Michael A.,Xie, Xiao-Song,De Brabander, Jef K.
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supporting information
p. 4393 - 4398
(2015/10/12)
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- Synthesis and biological evaluation of new fluorine substituted derivatives as angiotensin II receptor antagonists with anti-hypertension and anti-tumor effects
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The synthesis and pharmaceutical activity of new potent non-tetrazole angiotensin II (Ang II) receptor antagonists were described. These compounds were fluorine substituted derivatives of Losartan, Valsartan and Irbesartan with carboxylic acid group as re
- Da, Ya-Jing,Yuan, Wei-Dong,Xin, Ting,Nie, Yong-Yan,Ye, Ying,Yan, Yi-Jia,Liang, Li-Sha,Chen, Zhi-Long
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p. 7101 - 7111
(2013/01/15)
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- CERTAIN DIPEPTIDYL PEPTIDASE INHIBITORS
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Provided are certain dipeptidyl peptidase inhibitors, pharmaceutical compositions thereof, and methods of use therefor.
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Page/Page column 19
(2011/07/08)
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- MODULATORS OF 5-HT RECEPTORS AND METHODS OF USE THEREOF
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The present application relates to aryl- and heteroaryl-fused decahydropyrroloazepine, octahydrooxepinopyrrole, octahydropyrrolothiazepine dioxide, decahydrocyclohepta[c]pyrrole, and octahydrocyclohepta[c]pyrrole derivatives of formula (I), wherein R1,R2, R3, R4, R5, A, Y1, Y2, and Y3 are as defined in the specification. The present application also relates to compositions comprising such compounds, processes for making such compounds, and methods of treating disease conditions using such compounds and compositions, and methods for identifying such compounds.
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Page/Page column 135-136
(2010/12/18)
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- Umpolung direct arylation reactions: Facile process requiring only catalytic palladium and substoichiometric amount of silver salts
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An umpolung direct arylation process is described. The reaction requires only a catalytic amount of Pd(OAc)2 and a substoichiometric amount of silver salts, without any external base or ligand to proceed. The directed oxidative insertion of the transition metal followed by the coupling into the C-H bond of an unactivated arene has surprisingly not yet been reported, despite the clear advantages in the ease of starting material synthesis. The reaction is regioselective with regards to the arene partner, and the role of the acetate and carbonate groups has been elucidated. This methodology adds to the very few examples of benzene coupling without the inclusion of electron-withdrawing groups to increase acidity.
- Mousseau, James J.,Vallee, Frederic,Lorion, Melanie M.,Charette, Andre B.
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supporting information; experimental part
p. 14412 - 14414
(2010/12/24)
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- PROCESS FOR MAKING GLUCOCORTICOID RECEPTOR LIGANDS
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The invention encompasses a process for making 2-[1-phenyl-5-hydroxy-4alpha-methyl-hexahydrocyclopenta[f]indazol-5-yl]ethyl phenyl derivatives, which are glucocorticoid receptor ligands, useful for the treatment of inflammatory and immunological diseases.
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Page/Page column 20
(2009/05/30)
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- Arylaminoaryl-alkyl-substituted imidazolidine-2,4-diones, process for preparing them, medicaments comprising these compounds, and their use
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This invention relates to arylaminoaryl-alkyl-substituted imidazolidone-2,4-diones of formula (I) and also to their physiologically tolerated salts: Wherein R, R′, R1 to R10, A, D, E, G, L and p are as defined herein. The invention also relates to processes for preparing them, pharmaceutical compositions comprising them and their therapeutic use. The compounds are suitable, for example, as anti-obesity drugs and for treating cardiometabolic syndrome.
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Page/Page column 52
(2009/09/07)
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- 2-[1-PHENYL-5-HYDROXY OR METHOXY-4ALPHA-METHYL-HEXAHYDROCLOPENTA[F]INDAZOL-5-YL]ETHYL PHENYL DERIVATIVES AS GLUCOCORTICOID RECEPTOR LIGANDS
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The present invention is directed to 2- [l-phenyl-5 -hydroxy or methoxy-4alpha- methyl-hexahydrocyclopenta[f]indazol-5-yl]ethyl phenyl derivatives of formula I (I) as glucocorticoid receptor ligands useful for treating a variety of autoimmune and inflamma
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Page/Page column 52-53
(2008/12/05)
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- Synthesis of isotopically labelled (3-14C)- and (3,3- 2H2)-5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2690), a new antifungal agent for the potential treatment of onychomycosis
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5-Fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2690) is a new antifungal agent for the potential treatment of onychomycosis. During the preclinical development phase, it was necessary to synthesize the radioisotope [3-14C]-5-fluoro-1,3-dih
- Baker, Stephen J.,Zhang, Yong-Kang,Akama, Tsutomu,Wheeler, Conrad,Plattner, Jacob J.,Rosser, Richard M.,Reid, Ronald P.,Nixon, Neil S.
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p. 245 - 250
(2008/02/07)
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- ADAMANTYL DERIVATES AS P2X7 RECEPTOR ANTAGONISTS
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The invention provides compounds of formula (I) pharmaceutically acceptable salt or solvate thereof, in which R1, A1, m and A are as defined in the specification; a process for their preparation; pharmaceutical compositions containin
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Page/Page column 123-124
(2010/10/20)
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- Zirconocene-mediated and/or catalyzed unprecedented coupling reactions of alkoxymethyl-substituted styrene derivatives
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Reactions of o-(alkoxymethyl)styrene derivatives with a stoichiometric amount of zirconocenebutene complex (zirconocene equivalent, "Cp 2Zr") brought about an insertion of the zirconocene species into a benzylic carbon-oxygen bond. The oxidative insertion of Cp2Zr to the benzylic carbon-oxygen bond is a result of sequential reactions: (i) formation of zirconacyclopropane by the ligand exchange with o-(alkoxymethyl)styrene, (ii) elimination of the alkoxy group through an aromatic conjugate system giving metalated o-quinodimethane species, and (iii) transfer of zirconium metal to the benzylic position. Through use of a catalytic amount of "Cp2Zr", however, unprecedented homo-coupling reactions (dimerization) of o-(alkoxymethyl)styrene derivatives occurred to give a tetracyclic compound. On the other hand, reactions of o-(1-alkoxyisopropyl) styrene derivatives gave rise to the analogous tetracyclic compounds regardless of the amount of "Cp2Zr" (stoichiometric or catalytic). Heterocoupling product between o-(1-alkoxyisopropyl)styrene and styrene congeners was obtained in high cis stereo- and regioselectivity by treating o-(1-alkoxyisopropyl)styrene derivatives with "Cp2Zr" in the presence of an excess amount of styrene derivatives.
- Ikeuchi, Yutaka,Taguchi, Takeo,Hanzawa, Yuji
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p. 4354 - 4359
(2007/10/03)
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- NEW PYRIDIN-2-ONE COMPOUNDS USEFUL AS INHIBITORS OF THROMBIN
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There is provided a compound of formula I, wherein the dashed line, R1, R2, R3a, R3b, A, D, E, G and L have meanings given in the description, which compounds are useful as, or are useful as prodrugs of, competitive inhibitors of trypsin-like proteases, such as thrombin, and thus, in particular, in the treatment of conditions where inhibition of thrombin is beneficial (e.g. conditions, such as thrombo-embolisms, where inhibition of thrombin is required or desired, and/or conditions where anticoagulant therapy is indicated).
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Page/Page column 114
(2008/06/13)
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- Preparation of 2-aminomethyl-5-fluorobenzamides
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Benzamide compounds of Formula VII are prepared by reacting a benzoate compound of Formula V with an amine to obtain a benzamide compound of Formula VI, and then treating the benzamide VI with an amine deprotecting agent to obtain the benzamide VII; where
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