- 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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- Base- and Additive-Free Ir-Catalyzed ortho-Iodination of Benzoic Acids: Scope and Mechanistic Investigations
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A protocol for the C-H activation/iodination of benzoic acids catalyzed by a simple iridium complex has been developed. The method described in this paper allows the ortho-selective iodination of a variety of benzoic acids under extraordinarily mild conditions in the absence of any additive or base in 1,1,1,3,3,3-hexafluoroisopropanol as the solvent. The iridium catalyst used tolerates air and moisture, and selectively gives ortho-iodobenzoic acids with high conversions. Mechanistic investigations revealed that an Ir(III)/Ir(V) catalytic cycle operates, and that the unique properties of HFIP enables the C-H iodination using the carboxylic moiety as a directing group.
- Erbing, Elis,Sanz-Marco, Amparo,Vázquez-Romero, Ana,Malmberg, Jesper,Johansson, Magnus J.,Gómez-Bengoa, Enrique,Martín-Matute, Belén
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p. 920 - 925
(2018/02/14)
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- EGFR PROTEOLYSIS TARGETING CHIMERIC MOLECULES AND ASSOCIATED METHODS OF USE
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The present disclosure relates to bifunctional compounds, which find utility as modulators of receptor tyrosine kinase (RTK) proteins. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a ligand which binds to an E3 ubiquitin ligase and on the other end a moiety which binds a target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effectuate ubiquitination, and therefore, degradation (and inhibition) of the target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
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Paragraph 00757
(2018/07/29)
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- Pd-Catalyzed Selective Synthesis of Cyclic Sulfonamides and Sulfinamides Using K2S2O5 as a Sulfur Dioxide Surrogate
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A variety of cyclic sulfonamides and sulfinamides could be selectively synthesized under Pd catalysis using haloarenes bearing amino groups and a sulfur dioxide (SO2) surrogate. The amount of base was key in determining the selectivity. Mechanistic studies revealed that sulfinamides were initially formed via an unprecedented formal insertion of sulfur monoxide and were oxidized to sulfonamides in the presence of an iodide ion and DMSO.
- Konishi, Hideyuki,Tanaka, Hiromichi,Manabe, Kei
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supporting information
p. 1578 - 1581
(2017/04/13)
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- Direct Electrophilic C?H Alkynylation of Unprotected 2-Vinylanilines
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Unprotected aromatic amines can be used as directing groups in metal-catalyzed C?H alkynylations of alkenes. By using low amounts of an IrIIIcatalyst in combination with alkynylbenziodoxolones as electrophilic alkyne-transfer reagents, highly desirable 1,3-enynes were isolated in excellent yields of up to 98 % with Z stereoselectivity. A broad substrate scope as well as the high synthetic utility of the 1,3-enynes render this new method an efficient approach for the synthesis of five- and six-membered heterocycles. Further derivatizations of the 1,3-enynes to highly substituted quinolines through AuI- and N-bromosuccinimide-mediated exo-dig cyclizations were demonstrated.
- Caspers, Lucien D.,Finkbeiner, Peter,Nachtsheim, Boris J.
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supporting information
p. 2748 - 2752
(2017/03/08)
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- Heterocyclic compounds and uses thereof
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Heterocyclic entities that modulate PI3 kinase activity, pharmaceutical compositions containing the isoquinolone entities, and methods of using these chemical entities for treating diseases and conditions associated with P13 kinase activity are described
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Page/Page column 165; 166; 167
(2016/05/19)
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- HETEROCYCLIC COMPOUNDS AND USES THEREOF
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Compounds and pharmaceutical compositions that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including PI3 kinase activity, are described herein.
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-
Paragraph 00736; 00773
(2015/04/22)
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- DIFLUOROMETHYLENE COMPOUND
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The present invention relates to a compound having an URAT1 inhibitory activity, and to an URAT1 inhibitor, a blood uric acid level-reducing agent and a pharmaceutical composition containing the compound. More specifically, the present invention relates to a compound represented by the formula (I): wherein R1 is -Q1-A1 or the like; R2 is a hydrogen atom, a halogen atom, a lower alkyl group or the like; W1, W2, W3 and W4 are each independently a nitrogen atom or a methine group optionally having substituents, or the like; X and Y are each a single bond, an oxygen atom or the like; Z is a hydroxyl group or COOR3 or the like.
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Paragraph 0654; 0655
(2015/06/16)
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- PYRIMIDINE OR PYRIDINE DERIVATIVES USEFUL AS PI3K INHIBITORS
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Compounds (I) and pharmaceutical compositions that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including P13 kinase activity, are described herein.
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Paragraph 00590
(2015/11/23)
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- A simple and efficient two-step synthesis of 1,2,3-triiodoarenes via consecutive C-H iodination/ipso-Iododecarboxylation strategy: A potential application towards Ortho-diiodoarenes by Regioselective metal-iodine exchange reaction
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A general, robust, and efficient method for the conversion of benzoic acids to 1,2,3-triiodoarenes and 1,2,3-trihaloarenes via a two-step synthesis is reported. Commercially available benzoic acids were used that can allow the reactions to be performed on multi-gram scales with good-to-excellent yields. This report discloses a practical method for the synthesis of 1,2,3-triiodoarenes and 1,2,3-trihaloarenes that is general in scope, scalable, and easy to workup and purify. A potential application of the target compounds as precursors for novel regioselective metal-iodine exchange reaction of 1,2,3-triiodoarenes was also demonstrated. It provided ortho-diiodoaryl derivatives in a high regioselective fashion that are useful intermediates in synthesis and indeed are hard to synthesize by any other means.
- Al-Zoubi, Raed M.,Al-Mughaid, Hussein,McDonald, Robert
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p. 912 - 918
(2015/06/25)
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- Direct carbocyclizations of benzoic acids: Catalyst-controlled synthesis of cyclic ketones and the development of tandem aHH (acyl Heck-Heck) reactions
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The formation of exo-methylene indanones and indenones from simple ortho-allyl benzoic acid derivatives has been developed. Selective formation of the indanone or indenone products in these reactions is controlled by choice of ancillary ligand. This new process has a low environmental footprint as the products are formed in high yields using low catalyst loadings, while the only stoichiometric chemical waste generated from the reactants in the transformation is acetic acid. The conversion of the active cyclization catalyst into the Hermman-Beller palladacycle was exploited in a one-pot tandem acyl Heck-Heck (aHH) reaction, and utilized in the synthesis of donepezil. Carboxylic acids in aHH: Simple ortho-allyl benzoic acid derivatives have been utilized in an acyl Heck (aH) reaction to selectively form indanones and indenones. The conversion of the active cyclization catalyst into the Hermman-Beller palladacycle was exploited in a one-pot tandem acyl Heck-Heck (aHH) reaction to form two sp 2-sp2 bonds of (E)-trisubstituted olefins.
- Miles, Kelsey C.,Le, Chi,Stambuli, James P.
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supporting information
p. 11336 - 11339
(2014/10/16)
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- FAK AND FLT3 INHIBITORS
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The use of a compound of the formula (I): (Formula (I)) in the preparation of a medicament for treating Acute Myeloid Leukemia or a disease ameliorated by the inhibition of Flt3, or Flt3 and FAK.
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Page/Page column 96
(2014/03/22)
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- HETEROCYCLIC COMPOUNDS AND USES THEREOF
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Compounds and pharmaceutical compositions that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including PI3 kinase activity, are described herein.
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Paragraph 0794; 0849
(2013/10/22)
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- NOVEL INHIBITOR COMPOUNDS OF PHOSPHODIESTERASE TYPE 10A
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The present invention relates to novel carboxamide compounds, pharmaceutical compositions containing them, and their use in therapy. The compounds possess valuable therapeutic properties and are particularly suitable for treating or controlling medical disorders selected from neurological disorders and psychiatric disorders, for ameliorating the symptoms associated with such disorders and for reducing the risk of such disorders
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- FAK INHIBITORS
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A compound of the formula (I): where R1 or R2 is a cycle amine group and R5 is an aromatic group with a carbonyl containing substituent for use as a FAK inhibitor.
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Page/Page column 94
(2012/09/10)
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- Copper-catalyzed cross-coupling interrupted by an opportunistic smiles rearrangement: An efficient domino approach to dibenzoxazepinones
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Unexpected Smiles! An unusual and highly regioselective synthesis of dibenzoxazepinones by a domino sequence assisted by an unexpected Smiles rearrangement is reported. The process is effective on electronically differentiated phenols and shows a high tolerance to variation in the benzamide substituents. A plausible path for the reaction, supported by preliminary mechanistic data, is offered. Copyright
- Kitching, Matthew O.,Hurst, Timothy E.,Snieckus, Victor
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supporting information; experimental part
p. 2925 - 2929
(2012/05/04)
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- CERTAIN CHEMICAL ENTITIES, COMPOSITIONS AND METHODS
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Chemical entities that modulate PD kinase activity, pharmaceutical compositions containing the chemical entities, and methods of using these chemical entities for treating diseases and conditions associated with P13 kinase activity are described herein.
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Page/Page column 78-79
(2009/09/04)
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- Total synthesis of the aspercyclides
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Two different approaches to the eleven-membered biaryl ether lactones of the aspercyclide family are disclosed. The core regions of these highly strained targets, which are able to interfere with the binding of immunoglobulinE to its high affinity receptor, can either be forged by ring-closing olefin metathesis (RCM) or by a highly diastereoselective chromium-mediated Nozaki-Hiyama-Kishi (NHK) reaction. Whereas the RCM approach turned out to be responsive to minor changes in the substitution pattern of the substrate, the NHK route is more generally applicable. The preparation of the required cyclization precursor 43 hinged on a palladium-catalyzed orthoiodination reaction of 2-methylbenzoic acid, an efficient copper-catalyzed Ullmann coupling, and a Takai-Utimoto olefination as the key steps. Moreover, the esterification of the 2,6-disubstituted benzoic acid 34 with the sterically hindered secondary alcohol 37 was far from trivial. However, this and related transformations were accomplished by recourse to the corresponding acid fluorides, which provided excellent yields in cases in which the more commonly used acid chlorides or mixed anhydrides failed to afford any of the desiredproducts.
- Pospisil, Jiri,Mueller, Christoph,Fuerstner, Alois
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experimental part
p. 5956 - 5968
(2010/03/03)
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- PdII-catalyzed monoselective ortho halogenation of C-H bonds assisted by counter cations: A complementary method to directed ortho lithiation
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(Chemical Equation Presented) When the counterion counts: The yield and selectivity of the title transformation of benzoic acid derivatives were improved greatly by using tetraalkyl ammonium salts as additives (see scheme; monoselectivity: 5:1-18:1). These effects are attributed to the influence of counter cations. The halogenated products are versatile intermediates for the construction of substituted aromatic compounds. DMF=N,N-dimethylformamide.
- Mei, Tian-Sheng,Giri, Ramesh,Maugel, Nathan,Yu, Jin-Quan
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supporting information; experimental part
p. 5215 - 5219
(2009/04/11)
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- Process for the preparation of 2-halobenzoic acids
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The present invention provides a process for producing 2-halobenzoic acids of the general formula (I), characterized by reacting a benzoic acid of formula (II) with a halogenating agent in the presence of Pd catalyst: (wherein A is —OH, —OM (M is alkali metal), —N(R6)R7 (R6 and R7 are each H, C1-C6 alkyl, optionally substituted phenyl, or the like) ; R is H, C1-C6 alkyl, C1-C6 alkylcarbonyl, carboxyl, C1-C12 alkoxycarbonyl, optionally substituted phenylcarbonyl, or the like; n is 0 to 4; X is Cl, Br or I, or alternatively (R)n may be present on benzene-constituting carbon atoms adjacent to each other and form a C3-C4 alkylene- or C3-C4 alkenylene-fused ring).
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