- TAU-PROTEIN TARGETING COMPOUNDS AND ASSOCIATED METHODS OF USE
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The present disclosure relates to bifunctional compounds, which find utility as modulators of tan protein. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a VHL or cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds tan protein, such that tan protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of tan. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of tan protein. Diseases or disorders that result from aggregation or accumulation of tan protein are treated or prevented with compounds and compositions of the present disclosure.
- -
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Paragraph 1488; 1489
(2021/02/12)
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- Chemical degradation of androgen receptor (Ar) using bicalutamide analog–thalidomide protacs
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A series of PROTACs (PROteolysis-TArgeting Chimeras) consisting of bicalutamide analogs and thalidomides were designed, synthesized, and biologically evaluated as novel androgen receptor (AR) degraders. In particular, we found that PROTAC compound 13b could successfully demonstrate a targeted degradation of AR in AR-positive cancer cells and might be a useful chemical probe for the investigation of AR-dependent cancer cells, as well as a potential therapeutic candidate for prostate cancers.
- Kim, Ga Yeong,Song, Chae Won,Yang, Yo-Sep,Lee, Na-Rae,Yoo, Hyung-Seok,Son, Seung Hwan,Lee, Soo Jin,Park, Jong Seon,Lee, Jong Kil,Inn, Kyung-Soo,Kim, Nam-Jung
-
supporting information
(2021/05/26)
-
- Traceless Staudinger ligation enabled parallel synthesis of proteolysis targeting chimera linker variants
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A parallel, one-pot assembly approach to proteolysis targeting chimeras (PROTACs) is demonstrated utilizing activated esters generatedin situ, and traceless Staudinger ligation chemistry. The method described allows for rapid structure-activity relationship studies of PROTAC linker variants. Two previously studied systems, cereblon and BRD4 degraders, are examined as test cases for the synthetic method. The two related strategies to assemble PROTAC linker variants discussed can accommodate the chromotographic separations capabilities of labs of many sizes and incorporates commercially available degrader building blocks, thereby easing synthetic entry into PROTAC chemical space.
- Bemis, Troy A.,La Clair, James J.,Burkart, Michael D.
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supporting information
p. 1026 - 1029
(2021/02/06)
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- SELECTIVE HISTONE DEACETYLASE INHIBITORS FOR THE TREATMENT OF HUMAN DISEASE
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Selective HDAC inhibitors, and pharmaceutical compositions that include the same, are described herein for the treatment of cancer, immunological diseases, inflammatory diseases, and neurological diseases.
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Paragraph 0319
(2021/08/27)
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- GPX4 protein degradation agent, preparation method and application thereof, and antitumor cell drug
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The invention provides a GPX4 protein degradation agent, a preparation method thereof, and an anti-tumor cell drug, and belongs to the technical field of drug application. The GPX4 protein degradation agent provided by the invention has a protein degradation targeting chimera (PROTAC) molecular structure, a mother nucleus structure of the GPX4 protein degradation agent is used as a small molecule ligand for combining target protein, an A2 substituent is used as a small molecule ligand for combining an E3 ubiquitin ligase compound, and an A1 substituent is used as a connecting group for connecting the two ligands. The GPX4 protein degradation agent with the structure can specifically recognize GPX4 protein and effectively ubiquitinate and degrade the GPX4 protein, so that tumor cell ferroptosis is induced.
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Paragraph 0296-0297; 0304-0305
(2021/09/04)
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- Preparation method of lenalidomide
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The invention provides a preparation method of lenalidomide. The preparation method of the lenalidomide comprises the steps of preparing an intermediate 2-halogen methyl-3 methyl nitrobenzoate and anintermediate 3-amino piperidine-2,6-diketone, and preparing the lenalidomide by using the two intermediates. The preparation method of the lenalidomide is simple in steps, high in yield, low in cost,and beneficial to industrial production.
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Paragraph 0032; 0039-0040
(2019/11/20)
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- IMIDE-BASED MODULATORS OF PROTEOLYSIS AND METHODS OF USE
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The description relates to imide-based compounds, including bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the description provides compounds, which contain on one end a ligand which binds to the cereblon 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 effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation/inhibition of targeted polypeptides of nearly any type.
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Page/Page column 224; 230
(2019/08/12)
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- PROTAC-mediated crosstalk between E3 ligases
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Small-molecule heterobifunctional degraders can effectively control protein levels and are useful research tools. We assembled proteolysis targeting chimeras (PROTACs) from a cereblon (CRBN) and a von-Hippel-Lindau (VHL) ligase ligand and demonstrated a PROTAC-induced heterodimerization of the two E3 ligases leading to unidirectional and efficient degradation of CRBN.
- Steinebach, Christian,Kehm, Hannes,Lindner, Stefanie,Vu, Lan Phuong,K?pff, Simon,López Mármol, álvaro,Weiler, Corinna,Wagner, Karl G.,Reichenzeller, Michaela,Kr?nke, Jan,Gütschow, Michael
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supporting information
p. 1821 - 1824
(2019/02/12)
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- IRAK DEGRADERS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
- -
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Paragraph 1953; 1954
(2019/07/10)
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- Efficient Synthesis of Immunomodulatory Drug Analogues Enables Exploration of Structure–Degradation Relationships
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The immunomodulatory drugs (IMiDs) thalidomide, pomalidomide, and lenalidomide have been approved for the treatment of multiple myeloma for many years. Recently, their use as E3 ligase recruiting elements for small-molecule-induced protein degradation has led to a resurgence in interest in IMiD synthesis and functionalization. Traditional IMiD synthesis follows a stepwise route with multiple purification steps. Herein we describe a novel one-pot synthesis without purification that provides rapid access to a multitude of IMiD analogues. Binding studies with the IMiD target protein cereblon (CRBN) reveals a narrow structure–activity relationship with only a few compounds showing sub-micromolar binding affinity in the range of pomalidomide and lenalidomide. However, anti-proliferative activity as well as Aiolos degradation could be identified for two IMiD analogues. This study provides useful insight into the structure–degradation relationships for molecules of this type as well as a rapid and robust method for IMiD synthesis.
- Burslem, George M.,Ottis, Philipp,Jaime-Figueroa, Saul,Morgan, Alicia,Cromm, Philipp M.,Toure, Momar,Crews, Craig M.
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supporting information
p. 1508 - 1512
(2018/07/31)
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- SMALL MOLECULES AGAINST CEREBLON TO ENHANCE EFFECTOR T CELL FUNCTION
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Disclosed are small molecules against cereblon to enhance effector T cell function. Methodos of making thes molecules and methods of using them to treat various disease states are also disclosed.
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Page/Page column 136
(2017/10/11)
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- THALIDOMIDE ANALOGS AND METHODS OF USE
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Thalidomide analogs and methods of using the thalidomide analogs are disclosed. Some embodiments of the disclosed compounds exhibit anti- angiogenic and/or anti-inflammatory activity. Certain embodiments of the disclosed compounds are non-teratogenic.
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-
- Design, synthesis and biological evaluation of Lenalidomide derivatives as tumor angiogenesis inhibitor
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Lenalidomide is a type of immunomodulatory agent with anti-tumor activity by mainly expressed in the anti-angiogenesis. In order to enhance the pharmacological activity of Lenalidomide, a series of Lenalidomide derivatives were designed as tumor angiogenesis inhibitors. The potential anti-angiogenesis targets of Lenalidomide derivatives were virtual screened on Auto-Dock 4.0 by using reverse docking method. The six target proteins, such as vascular endothelial growth factor receptor, epidermal growth factor receptor, fibroblast growth factor receptor, BCR-ABL tyrosine kinase, p38 mitogen activated protein kinase and metal protein kinase, were chosen as the targets. The Lenalidomide derivatives were synthesized by alkylated, acylated or sulfonylated Lenalidomide and verified by the 1H NMR, 13C NMR and LC–MS. Their anti-cancer activities were detected by using CCK-8 in the esophageal carcinoma cell line EC9706. The results indicate that the inhibitory activities of Lenalidomide derivatives were higher than that of Lenalidomide.
- Hu, Shengquan,Yuan, Libin,Yan, Hong,Li, Zhigang
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p. 4075 - 4081
(2017/08/23)
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- Lenalidomide and lenalidomide intermediate preparation method
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A lenalidomide and lenalidomide intermediate preparation method includes the following four steps: (1) intramolecular ring-closure of N-Boc-glutamine methyl ester (I) in the presence of a condensing agent and a catalyst to obtain 3-Boc-imino-piperidine-2,6-dione (II); (2) deprotection reaction of the compound (II) obtained by the step (1) to obtain 3-(N-Boc-imino) - piperidine-2,6-dione (III); (3) condensation reaction of the compound (III) obtained by the step (2) and 2-bromomethyl-3-nitrobenzoate (IV) to obtain 3-( 7-nitro-3-oxo-1H-isoindole-2-yl)-piperidine-2,6-dione (V); and (4) nitro group reduction reaction of the compound (V) obtained by the step (3) to obtain lenalidomide (VI); and a synthetic route is shown in the specification.
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Paragraph 0023; 0024; 0025
(2016/10/31)
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- Practical synthesis of a phthalimide-based Cereblon ligand to enable PROTAC development
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The use of small molecules to regulate cellular levels of specific proteins is poised to become a powerful technique in the coming years. Critical to the success of any project utilizing such an approach will be the ability to synthesize libraries of candidate small molecules for testing in cellular systems. Herein, we describe a practical synthesis of a phthalimide-based scaffold, which can be easily diversified to make Cereblon-targeting PROTACs. We demonstrate the effectiveness of this approach by synthesizing a ‘PROTAC toolbox’ of four amines which can be coupled to inhibitors in a straightforward manner.
- Lohbeck, Jasmin,Miller, Aubry K.
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supporting information
p. 5260 - 5262
(2016/10/30)
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- New thalidomide analogues derived through Sonogashira or Suzuki reactions and their TNF expression inhibition profiles
-
A library of new thalidomide C4/5 analogues containing either a phenyl or alkyne tether were synthesized using Sonogashira or Suzuki cross coupling reactions from their aryl halogenated precursors. All thalidomide analogues were tested for their ability to inhibit the expression of the proinflammatory cytokine Tumor Necrosis Factor (TNF). More explicitly the use of a novel reporter system utilizing the promoter region of the TNF gene in a human T-cell line provided a rapid and effective measure of NFκB transcriptional activity. Several compounds either containing either an aryl-isobutyl or aryl-isopropoxy group were the most effective in inhibiting TNF expression, and were several times more active than thalidomide itself. Five of the more active derivatives indicated an apoptotic response while one of these compounds, containing an aldehyde tether, showed possible influence of cell cycling effects.
- Stewart, Scott G.,Braun, Carlos J.,Ng, Sze-Ling,Polomska, Marta E.,Karimi, Mahdad,Abraham, Lawrence J.
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supporting information; experimental part
p. 650 - 662
(2010/04/26)
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- Preliminary biological evaluations of new thalidomide analogues for multiple sclerosis application
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The present work deals with the synthesis of a new series of thalidomide derivatives for therapeutic applications. These compounds were evaluated in vitro on a human endothelial cell line EA.hy926 for their antiproliferative potential and in vivo on an experimental animal multiple sclerosis model called EAE as angiogenesis inhibitors. The preliminary results obtained on EAE assays seem to validate that anti-angiogenesis compounds could be promising tools for the treatment of MS.
- Contino-Pépin, Christiane,Parat, Audrey,Périno, Sandrine,Lenoir, Christine,Vidal, Michel,Galons, Hervé,Karlik, Stephen,Pucci, Bernard
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scheme or table
p. 878 - 881
(2009/09/06)
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- Syntheses of aromatic substituted 6′-thiothalidomides
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A resurgence of interest in thalidomide has occurred as a consequence of its diverse immunomodulatory and anticancer actions, which has fuelled interest in synthetic analogues with higher potencies or less undesirable side effect profiles. Several novel aromatic substituted 6′-thiothalidomides were synthesized whose synthetic route and strategy were developed on the basis of an analysis of reaction mechanisms. The regioselectivity of mono-thionation of aromatic substituted thalidomides with Lawesson's reagent is described, and the chemoselectivity of hydrogenation between the nitro group and 6′-thiocarbonyl group is discussed. Full characterization of eight substituted 6′-thiothalidomides is reported. Georg Thieme Verlag Stuttgart.
- Luo, Weiming,Yu, Qian-Sheng,Tweedie, David,Deschamps, Jeffery,Parrish, Damon,Holloway, Harold W.,Li, Yazhou,Brossi, Arnold,Greig, Nigel H.
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scheme or table
p. 3415 - 3422
(2009/05/26)
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- 5H-THIENO [3,4-c]PYRROLE-4, 6-DIONE DERIVATIVES AGAINST CELL RELEASING TUMOR NECROSIS FACTOR
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Taught are derivatives of 5H-thieno (3,4-c) pyrrole-4,6-dione, their organic, and inorganic salts, methods of synthesis of these derivatives, and their application as active pharmaceutical-ingredients useful as inhibitors of TNFα, the derivative being represented by the general formula (I): in which R1 represents H, C1-6alkyl, OR4, OC(O)R5, NO2, NHC(O)R6, or NR7R8; R2 represents H, a halogen, or C1-6alkyl; R3 represents H, methyl, isopropyl, allyl, benzyl, CH2CO2 (C1-6alkyl), or CH2(CH2)nR9; R4, R5, R6, R7, and R8 each independently and at each occurrence represents H, or C1-6alkyl; R9 represents H, C1-6alkyl, OH, OC1-6alkyl, NH2, NHC1-6alkyl, N(C1-6alkyl)2, or CO2(C1-6alkyl); and n represents 1, 2, 3, or 4.
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Page/Page column 28
(2008/12/08)
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- Hydrolyzed metabolites of thalidomide: Synthesis and TNF-α production-inhibitory activity
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Putative hydrolyzed metabolites of thalidomide were prepared and characterized, and their inhibitory activity on tumor necrosis factor (TNF)-α production in the human monocytic leukemia cell line THP-1 was evaluated. α-(2-Carboxybenzamido)glutarimide was a more potent TNF-α production inhibitor than thalidomide.
- Nakamura, Takanori,Noguchi, Tomomi,Miyachi, Hiroyuki,Hashimoto, Yuichi
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p. 651 - 654
(2008/02/08)
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- Synthesis and TNF expression inhibitory properties of new thalidomide analogues derived via Heck cross coupling
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A library of new thalidomide analogues containing an olefin functionality were synthesised using a Heck cross coupling reaction from their aryl halogenated precursor. All analogues were tested for their ability to inhibit the synthesis of the proinflammatory cytokine Tumour Necrosis Factor (TNF). Compounds 22, 29, 33 and 37 were the most effective in this assay inhibiting TNF expression 50%, 69%, 52% and 50%, respectively. Crown Copyright
- Stewart, Scott G.,Spagnolo, Daniel,Polomska, Marta E.,Sin, Melvin,Karimi, Mahdad,Abraham, Lawrence J.
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p. 5819 - 5824
(2008/03/13)
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- Mono- and dihydroxylated metabolites of thalidomide: Synthesis and TNF-α production-inhibitory activity
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Mono- and dihydroxylated metabolites of thalidomide were efficiently prepared and characterized, and their inhibitory activity on tumor necrosis factor (TNF)-α production in the human monocytic leukemia cell line THP-1 was evaluated. 5,N-Dihydroxythalidomide was a much more potent TNF-α production inhibitor than thalidomide.
- Nakamura, Takanori,Noguchi, Tomomi,Kobayashi, Hisayoshi,Miyachi, Hiroyuki,Hashimoto, Yuichi
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p. 1709 - 1714
(2007/10/03)
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- THALIDOMIDE ANALOGS
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Thalidomide analogs that modulate tumor necrosis factor alpha (TNF-α) activity and angiogenesis are disclosed. In particularly disclosed embodiments, the thalidomide analogs are isosteric sulfur-containing analogs. Also disclosed are methods of treating a subject with the analogs.
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Page/Page column 30; 53
(2008/06/13)
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- Inhibition of angiogenesis by THAM-derived cotelomers endowed with thalidomide moieties
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The synthesis of a tris(hydroxymethyl)acrylamidomethane (THAM)-derived cotelomer endowed with thalidomide units and a preliminary assessment of its biological activity are described. 4-Carboxy thalidomide and 4-(N-acryloyl) lysine thalidomide derivatives were prepared. The polymerization of these compounds with THAM in the presence of octanethiol as transfer reagent provided a water-soluble telomer bearing several thalidomide units. The ability of this telomer to inhibit angiogenesis in a mouse model of corneal neovascularization was compared to 4-carboxy thalidomide and thalidomide. A significant inhibition in area of neovascularization stimulated by a bFGF pellet was observed only in the mice treated with the telomer.
- Perino, Sandrine,Contino-Pepin, Christiane,Satchi-Fainaro, Ronit,Butterfield, Catherine,Pucci, Bernard
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p. 421 - 425
(2007/10/03)
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- Facile synthesis of an azido-labeled thalidomide analogue
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(Matrix presented) A five-step synthesis of an azido-thalidomide analogue is presented. The sequence requires cheap and readily available starting materials and reagents, and only two steps require purification. Additionally, the azido-labeled analogue possesses activity comparable to that of thalidomide in inhibiting the proliferation of human microvascular endothelial cells, thus providing impetus for its use as a potential photoaffinity label of thalidomide.
- Capitosti, Scott M.,Hansen, Todd P.,Brown, Milton L.
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p. 2865 - 2867
(2007/10/03)
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