cas 1448189-30-7, (4-(4-methylthiazol-5-yl)phenyl)methanamine

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MICROMOLECULAR COMPOUND SPECIFICALLYDEGRADING TAU PROTEIN, AND APPLICATION THEREOF
The present disclosure discloses a micromolecular compound specifically degrading tau protein, and an application thereof. The chemical structure of the micromolecular compound specifically degrading tau protein is TBM-L-ULM or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof, TBM being a tau protein-binding moiety, L being a linking group, and ULM being a ubiquitin ligase-binding moiety, the tau protein-binding moiety and the ubiquitin ligase-binding moiety being connected by means of the linking group. The micromolecular compound specifically degrading tau protein may increase tau protein degradation in a cell, thereby decreasing tau protein content.
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Paragraph 0047; 0075-0076

(2022/01/12)

Design, Synthesis, and Evaluation of VHL-Based EZH2 Degraders to Enhance Therapeutic Activity against Lymphoma
Traditional EZH2 inhibitors are developed to suppress the enzymatic methylation activity, and they may have therapeutic limitations due to the nonenzymatic functions of EZH2 in cancer development. Here, we report proteolysis-target chimera (PROTAC)-based EZH2 degraders to target the whole EZH2 in lymphoma. Two series of EZH2 degraders were designed and synthesized to hijack E3 ligase systems containing either von Hippel-Lindau (VHL) or cereblon (CRBN), and some VHL-based compounds were able to mediate EZH2 degradation. Two best degraders, YM181 and YM281, induced robust cell viability inhibition in diffuse large B-cell lymphoma (DLBCL) and other subtypes of lymphomas, outperforming a clinically used EZH2 inhibitor EPZ6438 (tazemetostat) that was only effective against DLBCL. The EZH2 degraders displayed promising antitumor activities in lymphoma xenografts and patient-derived primary lymphoma cells. Our study demonstrates that EZH2 degraders have better therapeutic activity than EZH2 inhibitors, which may provide a potential anticancer strategy to treat lymphoma.
Tu, Yalin,Sun, Yameng,Qiao, Shuang,Luo, Yao,Liu, Panpan,Jiang, Zhong-Xing,Hu, Yumin,Wang, Zifeng,Huang, Peng,Wen, Shijun
p. 10167 - 10184
(2021/07/26)

SMALL-MOLECULE INHIBITORS FOR THE Β-CATENIN/B-CELL LYMPHOMA 9 PROTEIN?PROTEIN INTERACTION
Disclosed are inhibitors for the β-catenin/B-cell lymphoma 9 interaction. The inhibitors are selective for β-catenin/B-cell lymphoma 9 over β-catenin/ E-cadherin PPI interaction. Methods of using the disclosed compounds to treat cancer are also disclosed.
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Page/Page column 162

(2021/04/01)

Reaction of Diisobutylaluminum Borohydride, a Binary Hydride, with Selected Organic Compounds Containing Representative Functional Groups
The binary hydride, diisobutylaluminum borohydride [(iBu)2AlBH4], synthesized from diisobutylaluminum hydride (DIBAL) and borane dimethyl sulfide (BMS) has shown great potential in reducing a variety of organic functional groups. This unique binary hydride, (iBu)2AlBH4, is readily synthesized, versatile, and simple to use. Aldehydes, ketones, esters, and epoxides are reduced very fast to the corresponding alcohols in essentially quantitative yields. This binary hydride can reduce tertiary amides rapidly to the corresponding amines at 25 °C in an efficient manner. Furthermore, nitriles are converted into the corresponding amines in essentially quantitative yields. These reactions occur under ambient conditions and are completed in an hour or less. The reduction products are isolated through a simple acid-base extraction and without the use of column chromatography. Further investigation showed that (iBu)2AlBH4 has the potential to be a selective hydride donor as shown through a series of competitive reactions. Similarities and differences between (iBu)2AlBH4, DIBAL, and BMS are discussed.
Amberchan, Gabriella,Snelling, Rachel A.,Moya, Enrique,Landi, Madison,Lutz, Kyle,Gatihi, Roxanne,Singaram, Bakthan
supporting information
p. 6207 - 6227
(2021/05/06)

Compound targeting ubiquitination degradation tyrosinase as well as preparation method and application thereof
A Tyr inhibitor kojic acid is covalently bound to a pomalidomide or VHL enzyme targeting ligand through a linkage chain to obtain a specific structure, and the preparation method is simple to operate and mild in condition. The generation of melanin is inhibited, the anti-melanin tumor effect is remarkable, and the safety period of vegetables and fruits can be remarkably prolonged. The compound targeted ubiquitination degradation tyrosinase provided by the invention has wide application prospects in medicine, food and cosmetics.
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Paragraph 0047; 0049

(2021/09/08)

TAU-PROTEIN TARGETING COMPOUNDS AND ASSOCIATED METHODS OF USE
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 0330

(2021/02/12)

GPER PROTEOLYTIC TARGETING CHIMERAS
A molecule comprising a G-protein coupled estrogen receptor (GPER) ligand coupled to a linker coupled to an E3 ubiquitin ligase ligand and methods of using the molecule are provided. In one embodiment, the GPER ligand is estradiol and the E3 ubiquitin lig
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Page/Page column 48

(2021/10/30)

BIFUNCTIONAL MOLECULES CONTAINING AN E3 UBIQUITINE LIGASE BINDING MOIETY LINKED TO A BCL6 TARGETING MOIETY
Bifunctional compounds, which find utility as modulators of B-cell lymphoma 6 protein (BCL6; target protein), are described herein. In particular, the bifunctional compounds of the present disclosure contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand that binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The bifunctional compounds of the present disclosure exhibit 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 00347; 00348

(2021/04/23)

Design, Synthesis, and Evaluation of WD-Repeat-Containing Protein 5 (WDR5) Degraders
Histone H3K4 methylation serves as a post-translational hallmark of actively transcribed genes and is introduced by histone methyltransferase (HMT) and its regulatory scaffolding proteins. One of these is the WD-repeat-containing protein 5 (WDR5) that has also been associated with controlling long noncoding RNAs and transcription factors including MYC. The wide influence of dysfunctional HMT complexes and the typically upregulated MYC levels in diverse tumor types suggested WDR5 as an attractive drug target. Indeed, protein-protein interface inhibitors for two protein interaction interfaces on WDR5 have been developed. While such compounds only inhibit a subset of WDR5 interactions, chemically induced proteasomal degradation of WDR5 might represent an elegant way to target all oncogenic functions. This study presents the design, synthesis, and evaluation of two diverse WDR5 degrader series based on two WIN site binding scaffolds and shows that linker nature and length strongly influence degradation efficacy.
D?lle, Anja,Adhikari, Bikash,Kr?mer, Andreas,Weckesser, Janik,Berner, Nicola,Berger, Lena-Marie,Diebold, Mathias,Szewczyk, Magdalena M.,Barsyte-Lovejoy, Dalia,Arrowsmith, Cheryl H.,Gebel, Jakob,L?hr, Frank,D?tsch, Volker,Eilers, Martin,Heinzlmeir, Stephanie,Kuster, Bernhard,Sotriffer, Christoph,Wolf, Elmar,Knapp, Stefan
supporting information
p. 10682 - 10710
(2021/05/29)

POLYCYCLIC COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF RAPIDLY ACCELERATED FIBROSARCOMA POLYPEPTIDES
The present disclosure relates to bifunctional compounds, ULM— L—PTM, which find utility as modulators of Rapidly Accelerated Fibrosarcoma (RAF, such as c-RAF, A- RAF and/or B-RAF; the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein RAF, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of 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, or the constitutive activation of the target protein, are treated or prevented with compounds and compositions of the present disclosure.
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Paragraph 1087; 1088

(2020/03/29)

Discovery of SK-575 as a Highly Potent and Efficacious Proteolysis-Targeting Chimera Degrader of PARP1 for Treating Cancers
The nuclear protein poly(ADP-ribose) polymerase-1 (PARP1) has a well-established role in the signaling and repair of DNA and is a validated therapeutic target for cancers and other human diseases. Here, we have designed, synthesized, and evaluated a series of small-molecule PARP1 degraders based on the proteolysis-targeting chimera (PROTAC) concept. Our efforts have led to the discovery of highly potent PARP1 degraders, as exemplified by compound 18 (SK-575). SK-575 potently inhibits the growth of cancer cells bearing BRCA1/2 mutations and induces potent and specific degradation of PARP1 in various human cancer cells even at low picomolar concentrations. SK-575 achieves durable tumor growth inhibition in mice when used as a single agent or in combination with cytotoxic agents, such as temozolomide and cisplatin. These data demonstrate that SK-575 is a highly potent and efficacious PARP1 degrader.
Cao, Chaoguo,Yang, Jie,Chen, Yong,Zhou, Peiting,Wang, Yingwei,Du, Wu,Zhao, Lifeng,Chen, Yuanwei
supporting information
p. 11012 - 11033
(2020/11/09)

Compound for targeted ubiquitination degradation of ERRalpha protein and pharmaceutical composition and application thereof
The invention provides a compound with a structure shown as a formula (I), which has the effects of inhibiting ERRalpha protein activity and degrading ERRalpha protein activity, has relatively strongsubtype selectivity and can also effectively inhibit tri
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Paragraph 0234-0235; 0248-0250

(2020/06/20)

Discovery of novel anti-angiogenesis agents. Part 11: Development of PROTACs based on active molecules with potency of promoting vascular normalization
Our recent investigation is focused on the discovery of anti-angiogenesis agents. Vascular normalization induced by anti-angiogenic agent appears to be a promising strategy. We have developed novel angiogenesis inhibitors with potency of promoting vascular normalization. Herein, we reported the design, synthesis and preliminary evaluation of proteolysis-targeting chimera (PROTACs) based on the previously developed anti-angiogenesis agents. Two PROTACs exhibited potent VEGFR-2 inhibition and anti-proliferative activity against HUVECs. Moreover, they were capable of reducing protein levels of VEGFR-2 in EA.hy926 cells without significant cytotoxicity against HEK293 cells. The novel PROTACs could be used to normalize the abnormal vessels, resulting in efficient delivery of drugs.
Shan, Yuanyuan,Si, Ru,Wang, Jin,Zhang, Qingqing,Li, Jing,Ma, Yuexiang,Zhang, Jie
(2020/08/05)

IRAK DEGRADERS AND USES THEREOF
The present invention provides compounds, compositions thereof, and methods of using the same.
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Paragraph 00962; 001409; 001412-001413

(2020/06/19)

IRAK DEGRADERS AND USES THEREOF
The present invention provides compounds, compositions thereof, and methods of using the same. The compounds include an IRAK binding moiety and a degradation inducing moiety (DIM). The DIM could be DTM a ligase binding moiety (LBM) or lysine mimetic. The compounds could be useful as IRAK protein kinase inhibitors and applied to IRAK mediated disorders.
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Paragraph 00794; 001114; 001117-001118

(2021/01/23)

AMIDE COMPOUND HAVING BET PROTEOLYSIS-INDUCING ACTION AND MEDICINAL APPLICATION THEREOF
The present invention aims to provide a compound that: has an excellent cytotoxic action on cancer cells, excellent induction of BET protein degradation in cancer cells, and an excellent binding-inhibiting action on BET protein and acetylated histone; and is effective as an anti-cancer agent, a BET protein degradation-inducing agent, or a BET protein inhibiting agent. A compound indicated in general formula (I) or a pharmacologically acceptable salt thereof. {In the formula, each symbol is as outlined in the Description.}
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Paragraph 0249; 0252-0254

(2020/01/31)

MODULATORS OF PROTEOLYSIS AND ASSOCIATED METHODS OF USE
The present disclosure relates to bifunctional compounds, which find utility as modulators of Kirsten rat sarcoma protein (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of 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, accumulation, and/or overactivation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
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Paragraph 00589-00590

(2019/10/29)

PROTAC-mediated crosstalk between E3 ligases
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
supporting information
p. 1821 - 1824
(2019/02/12)

IRAK DEGRADERS AND USES THEREOF
The present invention provides compounds, compositions thereof, and methods of using the same.
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Paragraph 2358; 2360

(2019/07/10)

6-oxohexahydropyrimidin derivative, as well as preparation method and pharmaceutical application thereof
The invention discloses a 6-oxohexahydropyrimidin derivative, and also discloses a preparation method of the derivative and an application of the derivative to preparation of drugs for preventing andtreating diseases such as cerebral apoplexy, cerebral is
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Paragraph 0077; 0079; 0082; 0083

(2019/05/08)

TAU-PROTEIN TARGETING PROTACS AND ASSOCIATED METHODS OF USE
The present disclosure relates to bifunctional compounds, which find utility as modulators of tau 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 tau protein, such that tau protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of tau. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of tau protein. Diseases or disorders that result from aggregation or accumulation of tau protein are treated or prevented with compounds and compositions of the present disclosure.
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Paragraph 0603; 0605

(2018/05/24)

Identification and Characterization of von Hippel-Lindau-Recruiting Proteolysis Targeting Chimeras (PROTACs) of TANK-Binding Kinase 1
Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that recruit an E3 ligase to a target protein to facilitate ubiquitination and subsequent degradation of that protein. While the field of targeted degraders is still relatively young, the potential for this modality to become a differentiated and therapeutic reality is strong, such that both academic and pharmaceutical institutions are now entering this interesting area of research. In this article, we describe a broadly applicable process for identifying degrader hits based on the serine/threonine kinase TANK-binding kinase 1 (TBK1) and have generalized the key structural elements associated with degradation activities. Compound 3i is a potent hit (TBK1 DC50 = 12 nM, Dmax = 96%) with excellent selectivity against a related kinase IKK?, which was further used as a chemical tool to assess TBK1 as a target in mutant K-Ras cancer cells.
Crew, Andrew P.,Raina, Kanak,Dong, Hanqing,Qian, Yimin,Wang, Jing,Vigil, Dominico,Serebrenik, Yevgeniy V.,Hamman, Brian D.,Morgan, Alicia,Ferraro, Caterina,Siu, Kam,Neklesa, Taavi K.,Winkler, James D.,Coleman, Kevin G.,Crews, Craig M.
p. 583 - 598
(2018/02/07)

MDM2-BASED MODULATORS OF PROTEOLYSIS AND ASSOCIATED METHODS OF USE
The description relates to MDM2 binding 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 MDM2 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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Paragraph 0376; 0378

(2017/01/31)

COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF BROMODOMAIN-CONTAINING PROTEINS
The present invention relates to bifunctional compounds, 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 present invention is directed to compounds, which contain on one end a VHL ligand which binds to the 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. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of targeted polypeptides.
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Paragraph 00194; 00196

(2017/03/21)

PROTEIN-PROTEIN INTERACTION INDUCING TECHNOLOGY
The present disclosure is based on the surprising and unexpected discovery that a ligand molecule with certain characteristics is able to bind to two protein molecules simultaneously and recruit them to form a transient or stable protein-protein interaction complex. The protein-protein interaction and other cross-domain interactions gained in this process contribute additional stabilization energy to the complex beyond the combination of the binary binding energies, and therefore, largely increase the binding potency of the ligand. Accordingly, the present disclosure provides a Protein-Protein Interaction Inducing Technology (PPIIT), which includes a method to design and identify the tripartite or bifunctional compounds and use such compounds to induce protein-protein interactions in various contexts. The present disclosure also provides a composition for the purpose of inducing protein-protein interactions.
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Paragraph 0191; 0193

(2017/10/17)

Design, Synthesis, and Characterization of Brequinar Conjugates as Probes to Study DHODH Inhibition
Brequinar, a potent dihydroorotate dehydrogenase (DHODH) inhibitor, has been evaluated in multiple clinical trials as a potential treatment for cancer. To further understand brequinar-based DHODH inhibition and DHODH′s therapeutic relevance in cancer, we
Madak, Joseph T.,Cuthbertson, Christine R.,Chen, Wenmin,Showalter, Hollis D.,Neamati, Nouri
p. 13875 - 13878
(2017/09/18)

ESTROGEN-RELATED RECEPTOR ALPHA BASED PROTAC COMPOUNDS AND ASSOCIATED METHODS OF USE
The present invention relates to bifunctional compounds, 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 present invention is directed to compounds, which contain on one end a VHL ligand which binds to the 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. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of targeted polypeptides.
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(2016/03/13)

COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF THE ANDROGEN RECEPTOR
The present invention relates to bifunctional compounds, which find utility to degrade and (inhibit) Androgen Receptor. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds Androgen Receptor such that Androgen Receptor is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of Androgen Receptor. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of Androgen Receptor.
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Paragraph 0399; 0402; 0403

(2016/08/17)

DERIVATIVES OF 1-[(CYCLOPENTYL OR 2-PYRROLIDINYL)CARBONYLAMINOMETHYL]-4-(1,3-THIAZOL-5-YL) BENZENE WHICH ARE USEFUL FOR THE TREATMENT OF PROLIFERATIVE, AUTOIMMUNE OR INFLAMMATORY DISEASES
There is provided novel small molecule E3 ubiquitin ligase protein binding ligand compounds, having utility in PROteolysis Targeted Chimeras (PROTACs), as well as processes for the preparation thereof, and use in medicine. There is particularly provided PROTACs which bind to a protein within the bromo- and Extra-terminal (BET) family of proteins, and especially to PROTACs including novel small molecule E3 ubiquitin ligase protein binding ligand compounds which selectively induce degradation of the BRD4 protein within the bromodomain of the BET family of proteins.
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Page/Page column 78; 79

(2016/10/24)

Compounds & Methods for the Enhanced Degradation of Targeted Proteins & Other Polypeptides by an E3 Ubiquitin Ligase
The present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins that are degraded and/or otherwise inhibited by bifunctional compounds of the present invention. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand that binds to the ubiquitin ligase and on the other end a moiety that 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. The present invention exhibits a broad range of pharmacological activities associated with compounds of the present invention, consistent with the degradation/inhibition of targeted polypeptides.
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(2014/12/09)

Structure-guided design and optimization of small molecules targeting the protein-protein interaction between the von hippel-lindau (VHL) E3 ubiquitin ligase and the hypoxia inducible factor (HIF) alpha subunit with in vitro nanomolar affinities
E3 ubiquitin ligases are attractive targets in the ubiquitin-proteasome system, however, the development of small-molecule ligands has been rewarded with limited success. The von Hippel-Lindau protein (pVHL) is the substrate recognition subunit of the VHL E3 ligase that targets HIF-1α for degradation. We recently reported inhibitors of the pVHL:HIF-1α interaction, however they exhibited moderate potency. Herein, we report the design and optimization, guided by X-ray crystal structures, of a ligand series with nanomolar binding affinities.
Galdeano, Carles,Gadd, Morgan S.,Soares, Pedro,Scaffidi, Salvatore,Van Molle, Inge,Birced, Ipek,Hewitt, Sarah,Dias, David M.,Ciulli, Alessio
p. 8657 - 8663
(2014/12/11)

Is NMR fragment screening fine-tuned to assess druggability of protein-protein interactions?
Modulation of protein-protein interactions (PPIs) with small molecules has been hampered by a lack of lucid methods capable of reliably identifying high-quality hits. In fragment screening, the low ligand efficiencies associated with PPI target sites pose
Dias, David M.,Van Molle, Inge,Baud, Matthias G. J.,Galdeano, Carles,Geraldes, Carlos F. G. C.,Ciulli, Alessio
supporting information
p. 23 - 28
(2014/02/14)

COMPOUNDS AND METHODS FOR THE INHIBITION OF VCB E3 UBIQUITIN LIGASE
The present invention relates to novel compounds which find utility as modulators, especially inhibitors of VCB E3 Ubiquitin Ligase and as bioactive agents for use as therapeutics for the stimulation of erythropoiesis in a patient or subject including inducement of EPO production in the patient or subject, for the treatment of chronic anemia and ischemia (limits brain injury during episodes of localized anemia, ischemia and/or stroke and damage to cardiovascular tissue during cardiovascular ischemia), as well as enhancing wound healing processes. Pharmaceutical compositions comprising effective amounts of compounds according to the present invention alone or in combination with an additional erythropoieses stimulating agent such as EPO under the tradename procrit or epogen or darbapoietin alfa under the tradename aranesp. Methods of stimulating erythropoiesis in a subject or patient, including increasing the number of red blood cells and/or hematocrit of the patient, treating anemia, including chronic anemia and anemia associated with chronic kidney disease, dialysis, and cancer chemotherapy, ischemia, stroke and damage to cardiovascular tissue during cardiovascular ischemia as well as enhancing wound healing processes and preventing/reducing scarring secondary to healing represent additional aspects of the present invention. Local enhancement of angiogenesis through induction of VEGF including wound healing and reduction of stent occlusion remain additional aspects of the present invention.
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Page/Page column 89

(2013/07/25)

Small-molecule inhibitors of the interaction between the E3 ligase VHL and HIF1α
By design: Novel small-molecule inhibitors of the interaction between the von Hippel-Lindau ligase (VHL) and its molecular target HIF1α, a transcription factor involved in oxygen sensing, have been developed and studied. The most potent inhibitor binds with an IC50 value of 0.9-μM and is thus the first sub-micromolar inhibitor of the VHL-HIF1α interaction. Copyright
Buckley, Dennis L.,Gustafson, Jeffrey L.,Van-Molle, Inge,Roth, Anke G.,Tae, Hyun Seop,Gareiss, Peter C.,Jorgensen, William L.,Ciulli, Alessio,Crews, Craig M.
p. 11463 - 11467
(2013/01/15)