当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > A Cereblon Modulator (CC-220) with Improved Degradation of Ikaros and Aiolos.

A Cereblon Modulator (CC-220) with Improved Degradation of Ikaros and Aiolos.

Abstract：

:The drugs lenalidomide and pomalidomide bind to the protein cereblon, directing the CRL4-CRBN E3 ligase toward the transcription factors Ikaros and Aiolos to cause their ubiquitination and degradation. Here we describe CC-220 (compound 6), a cereblon modulator in clinical development for systemic lupus erythematosis and relapsed/refractory multiple myeloma. Compound 6 binds cereblon with a higher affinity than lenalidomide or pomalidomide. Consistent with this, the cellular degradation of Ikaros and Aiolos is more potent and the extent of substrate depletion is greater. The crystal structure of cereblon in complex with DDB1 and compound 6 reveals that the increase in potency correlates with increased contacts between compound 6 and cereblon away from the modeled binding site for Ikaros/Aiolos. These results describe a new cereblon modulator which achieves greater substrate degradation via tighter binding to the cereblon E3 ligase and provides an example of the effect of E3 ligase binding affinity with relevance to other drug discovery efforts in targeted protein degradation.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Matyskiela ME,Zhang W,Man HW,Muller G,Khambatta G,Baculi F,Hickman M,LeBrun L,Pagarigan B,Carmel G,Lu CC,Lu G,Riley M,Satoh Y,Schafer P,Daniel TO,Carmichael J,Cathers BE,Chamberlain PP

doi

10.1021/acs.jmedchem.6b01921

subject

Has Abstract

pub_date

2018-01-25 00:00:00

pages

535-542

issue

2

eissn

0022-2623

issn

1520-4804

journal_volume

61

pub_type

杂志文章

相关文献

JOURNAL OF MEDICINAL CHEMISTRY文献大全
  • Design of N-Benzoxaborole Benzofuran GSK8175-Optimization of Human Pharmacokinetics Inspired by Metabolites of a Failed Clinical HCV Inhibitor.

    abstract：:We previously described the discovery of GSK5852 (1), a non-nucleoside polymerase (NS5B) inhibitor of hepatitis C virus (HCV), in which an N-benzyl boronic acid was essential for potent antiviral activity. Unfortunately, facile benzylic oxidation resulted in a short plasma half-life (5 h) in human volunteers, and a ba...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.8b01719

    authors： Chong PY,Shotwell JB,Miller J,Price DJ,Maynard A,Voitenleitner C,Mathis A,Williams S,Pouliot JJ,Creech K,Wang F,Fang J,Zhang H,Tai VW,Turner E,Kahler KM,Crosby R,Peat AJ

    更新日期：2019-04-11 00:00:00

  • Ocular Hypotensive Response in Nonhuman Primates of (8R)-1-[(2S)-2-Aminopropyl]-8,9-dihydro-7H-pyrano[2,3-g]indazol-8-ol a Selective 5-HT2 Receptor Agonist.

    abstract：:Recently, it has been reported that 5-HT2 receptor agonists effectively reduce intraocular pressure (IOP) in a nonhuman primate model of glaucoma. Although 1-[(2S)-2-aminopropyl]indazol-6-ol (AL-34662) was shown to have good efficacy in this nonhuman primate model of ocular hypertension as well as a desirable physicoc...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.5b00857

    authors： May JA,Sharif NA,McLaughlin MA,Chen HH,Severns BS,Kelly CR,Holt WF,Young R,Glennon RA,Hellberg MR,Dean TR

    更新日期：2015-11-25 00:00:00

  • Dopamine autoreceptor agonists: resolution and pharmacological activity of 2,6-diaminotetrahydrobenzothiazole and an aminothiazole analogue of apomorphine.

    abstract：:The enantiomers of the aminothiazole analogues of the known dopaminergic agonists apomorphine (1) and 2-aminohydroxytetralin (2) have been prepared. The absolute configurations of the enantiomers of 2,6-diaminotetrahydrobenzothiazole have been established by X-ray crystallographic analysis. Dopamine (DA) autoreceptor ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00386a009

    authors： Schneider CS,Mierau J

    更新日期：1987-03-01 00:00:00

  • N-(5,5-diacetoxypent-1-yl)doxorubicin: a new intensely potent doxorubicin analogue.

    abstract：:N-(5,5-Diacetoxypent-1-yl)doxorubicin (DAPDOX) (3), a new, water-soluble analogue of doxorubicin, has been synthesized by coupling doxorubicin with 5-oxopentane-1,1-diacetate in the presence of NaBH3CN. This analogue was designed to be converted to the corresponding aldehyde, N-(5-oxopent-1-yl)doxorubicin, in the pres...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00095a017

    authors： Cherif A,Farquhar D

    更新日期：1992-08-21 00:00:00

  • New Insights into Human 17β-Hydroxysteroid Dehydrogenase Type 14: First Crystal Structures in Complex with a Steroidal Ligand and with a Potent Nonsteroidal Inhibitor.

    abstract：:17β-HSD14 is a SDR enzyme able to oxidize estradiol and 5-androstenediol using NAD(+). We determined the crystal structure of this human enzyme as the holo form and as ternary complexes with estrone and with the first potent, nonsteroidal inhibitor. The structures reveal a conical, rather large and lipophilic binding ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.6b00293

    authors： Bertoletti N,Braun F,Lepage M,Möller G,Adamski J,Heine A,Klebe G,Marchais-Oberwinkler S

    更新日期：2016-07-28 00:00:00

  • Mapping the Efficiency and Physicochemical Trajectories of Successful Optimizations.

    abstract：:The practices and tactics employed in successful optimizations are examined, judged from the trajectories of ligand efficiency and property evolution. A wide range of targets is analyzed, encompassing a variety of hit finding methods (HTS, fragments, encoded library technology) and types of molecules, including those ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章,评审

    doi：10.1021/acs.jmedchem.8b00180

    authors： Young RJ,Leeson PD

    更新日期：2018-08-09 00:00:00

  • Syntheses and in vitro evaluation of water-soluble "cationic metalloporphyrin-ellipticine" molecules having a high affinity for DNA.

    abstract：:The synthesis of hybrid "cationic metalloporphyrin-intercalator" molecules is reported. These molecules are based on 9-methoxyellipticine as intercalator and tris-(4-N-methylpyridiniumyl)metalloporphyrins having a 4-aminophenyl or a 4-hydroxyphenyl group for the attachment of the linker. The effect of the length of li...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00107a005

    authors： Ding L,Etemad-Moghadam G,Cros S,Auclair C,Meunier B

    更新日期：1991-03-01 00:00:00

  • Antioxidant-Inspired Drug Discovery: Antitumor Metabolite Is Formed in Situ from a Hydroxycinnamic Acid Derivative upon Free-Radical Scavenging.

    abstract：:Cancer cells generally possess higher levels of reactive oxygen species than normal cells, and this can serve as a possible therapeutic target. In this proof-of-concept study, an antioxidant-inspired drug discovery strategy was evaluated using a hydroxycinnamic acid derivative. The processing of oxidized mixtures of p...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.8b01994

    authors： Fási L,Di Meo F,Kuo CY,Stojkovic Buric S,Martins A,Kúsz N,Béni Z,Dékány M,Balogh GT,Pesic M,Wang HC,Trouillas P,Hunyadi A

    更新日期：2019-02-14 00:00:00

  • Enkephalinase inhibitors. 1. 2,4-Dibenzylglutaric acid derivatives.

    abstract：:The synthesis of two new series of dicarboxylic acid dipeptides and two sulfhydryl-containing inhibitors are described. The in vitro enkephalinase inhibition data and some in vivo analgesic data are presented for these compounds. For the dibenzylglutaric acid series structure-activity relationships and in vivo analges...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00132a005

    authors： Ksander GM,Diefenbacher CG,Yuan AM,Clark F,Sakane Y,Ghai RD

    更新日期：1989-12-01 00:00:00

  • Synthesis and biological activity of a ketomethylene analogue of a tripeptide inhibitor of angiotensin converting enzyme.

    abstract：:An analogue of a tripeptide inhibitor of angiotensin converting enzyme, Bz-Phe-Gly-Pro, has been synthesized in which the amide bond connecting phenylalanine and glycine has been replaced by a ketomethylene group. This nonpeptide analogue, 20, shows more potent converting enzyme inhibiting activity, I50 = 0.07 microM,...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00186a020

    authors： Almquist RG,Chao WR,Ellis ME,Johnson HL

    更新日期：1980-12-01 00:00:00

  • Potential antitumor agents: synthesis and biological properties of aliphatic amino acid 9-hydroxyellipticinium derivatives.

    abstract：:Aliphatic amino acids glycine, alanine, valine, and leucine were conjugated to the antitumor drug N2-methyl-9-hydroxyellipticinium (NMHE) through a peroxidase-catalyzed oxidation reaction. NMR studies of the adducts so obtained have indicated (i) that the amino acids were linked to NMHE between the nitrogen of their p...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00375a013

    authors： Auclair C,Voisin E,Banoun H,Paoletti C,Bernadou J,Meunier B

    更新日期：1984-09-01 00:00:00

  • Design, Synthesis, and Structure-Activity Relationships of Pyridine-Based Rho Kinase (ROCK) Inhibitors.

    abstract：:The Rho kinases (ROCK1 and ROCK2) are highly homologous serine/threonine kinases that act on substrates associated with cellular motility, morphology, and contraction and are of therapeutic interest in diseases associated with cellular migration and contraction, such as hypertension, glaucoma, and erectile dysfunction...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.5b00424

    authors： Green J,Cao J,Bandarage UK,Gao H,Court J,Marhefka C,Jacobs M,Taslimi P,Newsome D,Nakayama T,Shah S,Rodems S

    更新日期：2015-06-25 00:00:00

  • Direct NMR Probing of Hydration Shells of Protein Ligand Interfaces and Its Application to Drug Design.

    abstract：:Fragment-based drug design exploits initial screening of low molecular weight compounds and their concomitant affinity improvement. The multitude of possible chemical modifications highlights the necessity to obtain structural information about the binding mode of a fragment. Herein we describe a novel NMR methodology...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.7b00845

    authors： Geist L,Mayer M,Cockcroft XL,Wolkerstorfer B,Kessler D,Engelhardt H,McConnell DB,Konrat R

    更新日期：2017-11-09 00:00:00

  • Discovery of 6alpha-ethyl-23(S)-methylcholic acid (S-EMCA, INT-777) as a potent and selective agonist for the TGR5 receptor, a novel target for diabesity.

    abstract：:In the framework of the design and development of TGR5 agonists, we reported that the introduction of a C(23)(S)-methyl group in the side chain of bile acids such as chenodeoxycholic acid (CDCA) and 6-ethylchenodeoxycholic acid (6-ECDCA, INT-747) affords selectivity for TGR5. Herein we report further lead optimization...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm901390p

    authors： Pellicciari R,Gioiello A,Macchiarulo A,Thomas C,Rosatelli E,Natalini B,Sardella R,Pruzanski M,Roda A,Pastorini E,Schoonjans K,Auwerx J

    更新日期：2009-12-24 00:00:00

  • 125I-labeled 8-phenylxanthine derivatives: antagonist radioligands for adenosine A1 receptors.

    abstract：:A series of 8-phenylxanthine derivatives has been synthesized with oxyacetic acid on the para phenyl position to increase aqueous solubility and minimize nonspecific binding and iodinatable groups on the 1- or 3-position of the xanthine ring. The structure-activity relationship for binding of these compounds to A1 ade...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00399a010

    authors： Linden J,Patel A,Earl CQ,Craig RH,Daluge SM

    更新日期：1988-04-01 00:00:00

  • Discovery and Development of S6821 and S7958 as Potent TAS2R8 Antagonists.

    abstract：:In humans, bitter taste is mediated by 25 TAS2Rs. Many compounds, including certain active pharmaceutical ingredients, excipients, and nutraceuticals, impart their bitter taste (or in part) through TAS2R8 activation. However, effective TAS2R8 blockers that can either suppress or reduce the bitterness of these compound...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.0c00388

    authors： Fotsing JR,Darmohusodo V,Patron AP,Ching BW,Brady T,Arellano M,Chen Q,Davis TJ,Liu H,Servant G,Zhang L,Williams M,Saganich M,Ditschun T,Tachdjian C,Karanewsky DS

    更新日期：2020-05-14 00:00:00

  • On sampling of fragment space.

    abstract：:Fragment-based lead discovery has over the years matured into an attractive alternative to high-throughput screening (HTS) for lead generation. Several techniques for screening libraries of typically 10(3)-10(4) fragments have been reported. In this work, the practical success rates that can be expected from the scree...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm0700316

    authors： Makara GM

    更新日期：2007-07-12 00:00:00

  • Recent Advances of Colony-Stimulating Factor-1 Receptor (CSF-1R) Kinase and Its Inhibitors.

    abstract：:Colony stimulation factor-1 receptor (CSF-1R), which is also known as FMS kinase, plays an important role in initiating inflammatory, cancer, and bone disorders when it is overstimulated by its ligand, CSF-1. Innate immunity, as well as macrophage differentiation and survival, are regulated by the stimulation of the C...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章,评审

    doi：10.1021/acs.jmedchem.7b00873

    authors： El-Gamal MI,Al-Ameen SK,Al-Koumi DM,Hamad MG,Jalal NA,Oh CH

    更新日期：2018-07-12 00:00:00

  • Design, synthesis, and biological activity of a novel series of human sirtuin-2-selective inhibitors.

    abstract：:Selective inhibitors of human sirtuin 2 (SIRT2), a deacetylase, are candidate therapeutic agents for neurodegenerative diseases such as Parkinson's disease and Huntington's disease as well as potential tools for elucidating the biological functions of SIRT2. On the basis of homology models of SIRT1 and SIRT2, we desig...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm3002108

    authors： Suzuki T,Khan MN,Sawada H,Imai E,Itoh Y,Yamatsuta K,Tokuda N,Takeuchi J,Seko T,Nakagawa H,Miyata N

    更新日期：2012-06-28 00:00:00

  • Synthesis and antitussive activity of aminotetra- (and -hexa-) hydrodibenzofurans.

    abstract：:The synthesis of a novel series of antitussive agents is described. Two series of amino-substituted tetra- and hexahydrodibenzofurans were prepared and examined for antitussive activity in the guinea pig after cough elicited by electrical stimulation of the vagus nerve. A significant level of activity, comparable with...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00212a003

    authors： Matharu SS,Rowlands DA,Taylor JB,Westwood R

    更新日期：1977-02-01 00:00:00

  • Nuclear magnetic resonance and molecular modeling study on mycophenolic acid: implications for binding to inosine monophosphate dehydrogenase.

    abstract：:The conformation of the sodium salt of mycophenolic acid (MPA), a potent inhibitor of inosine monophosphate dehydrogenase (IMPD), derived from 1D DIFNOE and 2D ROESY experiments in water and molecular dynamics (MD) is described. The hexenoic acid side chain conformation consistent with the NMR data was similar to that...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm950600m

    authors： Makara GM,Keserû GM,Kajtár-Peredy M,Anderson WK

    更新日期：1996-03-15 00:00:00

  • Antipsoriatic anthrones with modulated redox properties. 2. Novel derivatives of chrysarobin and isochrysarobin--antiproliferative activity and 5-lipoxygenase inhibition.

    abstract：:A novel series of 2- and 3-substituted 1,8-dihydroxy-9(10H)-anthracenones were synthesized and tested for their inhibitory activity against 5-lipoxygenase (5-LO) in bovine polymorphonuclear leukocytes and the growth of human keratinocytes. Structure-activity relationships are discussed with respect to the following re...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00037a017

    authors： Müller K,Leukel P,Ziereis K,Gawlik I

    更新日期：1994-05-27 00:00:00

  • Discovery of a Novel Inhaled PI3Kδ Inhibitor for the Treatment of Respiratory Diseases.

    abstract：:Oral PI3Kδ inhibitors such as Idelalisib and Duvelisib have shown efficacy as anticancer agents and Idelalisib has been approved for the treatment of three B-cell cancers. However, Idelalisib has a black box warning on its product label regarding the risks of fatal and serious toxicities including hepatic toxicity, se...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.8b00873

    authors： Erra M,Taltavull J,Bernal FJ,Caturla JF,Carrascal M,Pagès L,Mir M,Espinosa S,Gràcia J,Domínguez M,Sabaté M,Paris S,Maldonado M,Hernández B,Bravo M,Calama E,Miralpeix M,Lehner MD,Calbet M

    更新日期：2018-11-08 00:00:00

  • Discovery of 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo[h][1,6]naphthyridin-2(1H)-one as a highly potent, selective mammalian target of rapamycin (mTOR) inhibitor for the treatment of cancer.

    abstract：:The mTOR protein is a master regulator of cell growth and proliferation, and inhibitors of its kinase activity have the potential to become new class of anticancer drugs. Starting from quinoline 1, which was identified in a biochemical mTOR assay, we developed a tricyclic benzonaphthyridinone inhibitor 37 (Torin1), wh...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm101144f

    authors： Liu Q,Chang JW,Wang J,Kang SA,Thoreen CC,Markhard A,Hur W,Zhang J,Sim T,Sabatini DM,Gray NS

    更新日期：2010-10-14 00:00:00

  • Quantitative analyses of aggregation, autofluorescence, and reactivity artifacts in a screen for inhibitors of a thiol protease.

    abstract：:The perceived and actual burden of false positives in high-throughput screening has received considerable attention; however, few studies exist on the contributions of distinct mechanisms of nonspecific effects like chemical reactivity, assay signal interference, and colloidal aggregation. Here, we analyze the outcome...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm901070c

    authors： Jadhav A,Ferreira RS,Klumpp C,Mott BT,Austin CP,Inglese J,Thomas CJ,Maloney DJ,Shoichet BK,Simeonov A

    更新日期：2010-01-14 00:00:00

  • Synthesis and bioevaluation of delta 7-5-desaturase inhibitors, an enzyme late in the biosynthesis of the fungal sterol ergosterol.

    abstract：:Ergosterol, the predominant sterol of fungi, is postulated to have many cellular functions which include a bulk membrane role and a regulatory role. Studies with sterol auxotrophs show that, even in the presence of sterols which can fulfill the bulk membrane requirements, a small concentration of ergosterol is absolut...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm9605851

    authors： Goldstein AS,Frye LL

    更新日期：1996-12-20 00:00:00

  • Zwitterionic 3'-O-acyl derivatives of thymidine 5'-phosphate as potential sources of intracellular thymidine 5'-phosphate in cells in culture.

    abstract：:A convenient route is described for attachment of acyl groups CO(CH2)nN(Et)2(CH2)mNH(Et)2 (n = 3, m = 2; n = 4, m = 2-4), CO(CH2)nN(Et)2(CH2)mNEt3 (n = 4, m = 2-4), or CO(CH2)4N(CH2CH2)3N(CH2)nCH3 (n = 1 or 9) to O-3' of thymidine 5'-phosphate (TMP). The compounds are prototypes of 5'-nucleotide derivatives in which t...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00155a033

    authors： Chawla RR,Freed JJ,Kappler F,Hampton A

    更新日期：1986-05-01 00:00:00

  • Identification, synthesis, and pharmacological evaluation of tetrahydroindazole based ligands as novel antituberculosis agents.

    abstract：:The resurgence of tuberculosis (TB), the incidence of drug-resistant strains of Mycobacterium tuberculosis (MTB), and the coinfection between TB and HIV have led to serious infections, high mortality, and a global health threat, resulting in the urgent search for new classes of antimycobacterial agents. Herein, we rep...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm901235p

    authors： Guo S,Song Y,Huang Q,Yuan H,Wan B,Wang Y,He R,Beconi MG,Franzblau SG,Kozikowski AP

    更新日期：2010-01-28 00:00:00

  • Quinazoline antifolates inhibiting thymidylate synthase: 2-desamino derivatives with enhanced solubility and potency.

    abstract：:The poor solubility of the thymidylate synthase (TS) inhibiting antifolate 10-propargyl-5,8-dideazafolic acid has posed problems for its clinical use and is probably responsible for its renal toxicity. The insolubility is caused by the 2-amino-3,4-dihydro-4-oxopyrimidine moiety of the drug which stabilizes the solid s...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00124a018

    authors： Jones TR,Thornton TJ,Flinn A,Jackman AL,Newell DR,Calvert AH

    更新日期：1989-04-01 00:00:00

  • Two analogues of fenarimol show curative activity in an experimental model of Chagas disease.

    abstract：:Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is an increasing threat to global health. Available medicines were introduced over 40 years ago, have undesirable side effects, and give equivocal results of cure in the chronic stage of the disease. We report the development of two compoun...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm401610c

    authors： Keenan M,Chaplin JH,Alexander PW,Abbott MJ,Best WM,Khong A,Botero A,Perez C,Cornwall S,Thompson RA,White KL,Shackleford DM,Koltun M,Chiu FC,Morizzi J,Ryan E,Campbell M,von Geldern TW,Scandale I,Chatelain E,Charman

    更新日期：2013-12-27 00:00:00