Abstract：
:Targeted protein degradation with bifunctional degraders is positioned as a remarkable game-changing strategy to control cellular protein levels and promises a new therapeutic modality in drug discovery. Light activation of a degrader to achieve exquisite spatiotemporal control over protein stability in cells has attracted the interest of multiple research groups, with recent reports demonstrating optical control of proteolysis with chimeric molecules bearing photolabile or photoswitchable motifs. In this context of targeted proteolysis research spurring the emergence of innovative tools, we examine the design, synthesis, and properties of light-activated degraders. The significant impact of this approach in regulating disease-relevant protein levels in a light-dependent manner is highlighted with key examples, and future developments to fully harness the potential of light-induced protein degradation with photoactive bifunctional molecules are discussed.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Kounde CS,Tate EWdoi
10.1021/acs.jmedchem.0c01542subject
Has Abstractpub_date
2020-12-24 00:00:00pages
15483-15493issue
24eissn
0022-2623issn
1520-4804journal_volume
63pub_type
杂志文章abstract：:The synthesis of five amino phosphorus derivatives, 1a-e, is described. The derivatives were incorporated into a series (18) of analogues of the 5-14 portion of angiotensinogen, in most cases at the scissile Leu-Val bond. The resultant compounds were tested in vitro for their ability to inhibit human plasma renin. Rep...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00127a041
更新日期：1989-07-01 00:00:00
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
更新日期：1994-05-27 00:00:00
abstract：:Regioselective syntheses of substituted 2-chloroquinoxalines and derived 2-(1-piperazinyl)quinoxalines are described. Selectivity in regards to serotonin reuptake blocking and serotoninmimetic activities of the piperazinylquinoxalines is reported. In general, introduction of a 6-substituent into the piperazinylquinoxa...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00133a019
更新日期：1981-01-01 00:00:00
abstract：:Tipifarnib (R115777), an inhibitor of human protein farnesyltransferase (PFT), is shown to be a highly potent inhibitor of Trypanosoma cruzi growth (ED(50) = 4 nM). Surprisingly, this is due to the inhibition of cytochrome P450 sterol 14-demethylase (CYP51, EC 1.14.13.70). Homology models of the T. cruzi CYP51 were us...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm050441z
更新日期：2005-08-25 00:00:00
abstract：:Type II beta-turn mimics and polyproline II helix mimics based upon diastereoisomeric 5.6.5 spiro bicyclic scaffolds have provided two pairs of Pro-Leu-Gly-NH(2) (PLG) peptidomimetics with contrasting dopamine receptor modulating activities. Compounds 1a and 3a were found to be positive allosteric modulators of the do...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm801575w
更新日期：2009-04-09 00:00:00
abstract：:In 1994, following work from this laboratory, it was reported that estrone-3-O-sulfamate irreversibly inhibits a new potential hormone-dependent cancer target steroid sulfatase (STS). Subsequent drug discovery projects were initiated to develop the core aryl O-sulfamate pharmacophore that, over some 20 years, have led...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b00386
更新日期：2015-10-08 00:00:00
abstract：:We disclose a novel series of indenopyrazole-based cyclin-dependent kinase (CDK) inhibitors. Kinetic experiments confirmed our initial molecular modeling studies that the compounds are competitive with respect to adenosine 5'-triphosphate (ATP) and bind in the kinase ATP pocket. A unique combination of active pharmaco...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm020171+
更新日期：2002-11-21 00:00:00
abstract：:(N)-Methanocarba nucleosides containing bicyclo[3.1.0]hexane replacement of the ribose ring previously demonstrated selectivity as A(3) adenosine receptor (AR) agonists (5'-uronamides) or antagonists (5'-truncated). Here, these two series were modified in parallel at the adenine C2 position. N(6)-3-Chlorobenzyl-5'-N-m...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm900426g
更新日期：2009-12-10 00:00:00
abstract：:A variety of nonsteroidal systems can function as ligands for the estrogen receptor (ER), in some cases showing selectivity for one of the two ER subtypes, ER alpha or ER beta. We have prepared a series of heterocycle-based (furans, thiophenes, and pyrroles) ligands for the estrogen receptor and assessed their behavio...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm010211u
更新日期：2001-11-08 00:00:00
abstract：:A novel series of C(3)-substituted piperdinylindoles were developed as nociceptin opioid receptor (NOP) partial agonists to explore a pharmacological hypothesis that NOP partial agonists would afford a dual pharmacological action of attenuating Parkinson's disease (PD) motor symptoms and development of levodopa-induce...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b02134
更新日期：2020-03-12 00:00:00
abstract：:On the basis of our previous observation that N1-alkyl substituted chlorpropamide derivatives when administered to rats nonenzymatically eliminated n-propyl isocyanate, a known inhibitor of aldehyde dehydrogenase (AlDH), we have synthesized other latentiated n-propyl isocyanates as in vivo inhibitors of AlDH. N1-Allyl...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00050a018
更新日期：1994-11-25 00:00:00
abstract：:A variety of esters of methyldopa was synthesized with the objective of obtaining derivatives that would be more efficiently absorbed from the gastrointestinal tract than the free amino acid and would undergo conversion to methyldopa readily in the blood or target tissues. Two of the esters, alpha-pivaloyloxyethyl (4u...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00206a006
更新日期：1978-08-01 00:00:00
abstract：:A series of tricyclic indole-2-carboxylic acid derivatives were synthesized and evaluated by the radioligand binding assay and the anticonvulsant effects in the mouse NMDA-induced seizure model. Among them, derivatives of 3S-(-)-4 such as 3a, 3f, and 3g which had certain zwitterionic anilides showed high affinity to t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm020239l
更新日期：2003-02-27 00:00:00
abstract：:A combinatorial library of quinone-polyamine conjugates designed to optimize the antitrypanosomatid profile of hit compounds 1 and 2 has been prepared by a solid-phase approach. The conjugates were evaluated against the three most important human trypanosomatid pathogens (Trypanosoma brucei rhodesiense, Trypanosoma cr...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm301112z
更新日期：2012-12-13 00:00:00
abstract：:We synthesized 5-allyl-1-methyl-5-(m-trifluoromethyl-diazirynylphenyl)barbituric acid (14), a trifluoromethyldiazirine-containing derivative of general anesthetic mephobarbital, separated the racemic mixture into enantiomers by chiral chromatography, and determined the configuration of the (+)-enantiomer as S by X-ray...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm300631e
更新日期：2012-07-26 00:00:00
abstract：:The endocannabinoid 2-arachidonoylglycerol (2-AG) plays a major role in many physiological processes, and its action is quickly terminated via enzymatic hydrolysis catalyzed by monoglyceride lipase (MGL). Regulating its endogenous level could offer therapeutic opportunities; however, few selective MGL inhibitors have ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm900461w
更新日期：2009-12-10 00:00:00
abstract：:DoMCoSAR is a novel approach for statistically determining the docking mode that is consistent with a structure-activity relationship. The approach establishes the binding mode for the compounds in a chemical series with the assumption that all molecules exhibit the same binding mode. It involves three stages. In the ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm990609e
更新日期：2000-08-10 00:00:00
abstract：:Several derivatives of 4,5-disubstituted imidazole, 2,4,5-trisubstituted pyrimidine, 2-substituted purine, thiazolo[3,2-alpha]purine, [1,3]thiazino[3,2-alpha]purine, thiazolo[2,3-i]purine, [1,3]thiazino-[2,3-i]purine, and 6-substituted pyrazolo[3,4-d]pyrimidine were synthesized and tested as inhibitors of the xanthine...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm950876u
更新日期：1996-06-21 00:00:00
abstract：:As a continuation of our efforts to develop innovative ligands for D(3), 5-HT(1A), and 5-HT(2A) receptors with low propensity to block hERG channels, we propose a series bishetero(homo)arylpiperazines 5a-m as novel and potent multifunctional ligands characterized by low occupancy at D(2) and 5-HT(2C) receptors. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm100294b
更新日期：2010-06-24 00:00:00
abstract：:Ligand-induced stabilization of G-quadruplex structures formed by the human telomeric DNA is an active area of research. The compounds which stabilize the G-quadruplexes often lead to telomerase inhibition. Herein we present the results of interaction of new monomeric and dimeric ligands having 1,3-phenylene-bis(piper...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm200860b
更新日期：2012-04-12 00:00:00
abstract：:In this report, we describe the synthesis of a new series of small amphiphilic aromatic compounds that mimic the essential properties of cationic antimicrobial peptides using Suzuki-Miyaura coupling. The new design allowed the easy tuning of the conformational restriction, controlled by introduction of intramolecular ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm101410t
更新日期：2011-04-14 00:00:00
abstract：:Computational ligand-protein docking is routinely used for binding mode prediction. We have quantified the effect of considering multiple docking solutions on the success rate of obtaining the crystallographic binding mode. By selection of a small set of representatives, the experimentally observed binding mode can be...
journal_title：Journal of medicinal chemistry
pub_type： 信件
doi：10.1021/jm0498147
更新日期：2004-06-17 00:00:00
abstract：:The chemical synthesis of 2-[(2,6-dichloro-4-iodophenyl)imino]imidazolidine (PIC) and its radioiodinated analogue [125I]PIC is described. PIC was synthesized from 2,6-dichloroaniline in five synthetic steps. This agent displayed a high affinity for the alpha 2-adrenergic receptor (IC50 = 1.5 nM) in competitive binding...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00390a021
更新日期：1987-07-01 00:00:00
abstract：:A series of novel 3-quinolinecarboxamides that are structurally similar to the quinolone class of antibacterial agents possess excellent antiherpetic properties. By modifying the quinoline ring at the 1-, 2-, 3-, and 7-positions, analogues were identified that have up to 5-fold increased HSV-2 plaque-reduction potency...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00063a008
更新日期：1993-05-28 00:00:00
abstract：:Fifteen quinolizidine derivatives have been tested for antiarrhythmic, inotropic, and chronotropic effects on isolated guinea pig (gp) heart tissues and to assess calcium antagonist activity. All compounds exhibited from moderate to high antiarrhythmic activity, and five of them (3, 4, 6, 13, and 15) were more active ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm100298d
更新日期：2010-06-24 00:00:00
abstract：:A novel series of pyridazinone-functionalized phenylalanine analogues was prepared and evaluated for inhibition of cellular adhesion mediated by alpha4beta1/VCAM-1 and alpha4beta7/MAdCAM-1 interactions. Concise syntheses were developed and applied for exploration of structure-activity relationships pertaining to the p...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm060031q
更新日期：2006-06-01 00:00:00
abstract：:Biphenyl-4-carboxylic acid-[2-(1H-indol-3-yl)-ethyl]-methylamide 1 (CA224) is a nonplanar analogue of fascaplysin (2) that specifically inhibits Cdk4-cyclin D1 in vitro. Compound 1 blocks the growth of cancer cells at G0/G1 phase of the cell cycle. It also blocks the cell cycle at G2/M phase, which is explained by the...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm5014743
更新日期：2014-11-26 00:00:00
abstract：:The pharmaceutical industry has recognized that many drug-like molecules can self-aggregate in aqueous media and have physicochemical properties that skew experimental results and decisions. Herein, we introduce the use of a simple NMR strategy for detecting the formation of aggregates using dilution experiments that ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm400535b
更新日期：2013-06-27 00:00:00
abstract：:Photodynamic therapy (PDT) as a rising platform of the cancer treatment method is receiving increased attention. Through systematic evaluation of halogen substitution on aza-4,4-difluoro-4-bora-3a,4a-diaza-s-indacenes (BODIPY), we have found that monoiodo-derived aza-BODIPYs provided greater efficacy than other haloge...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c00882
更新日期：2020-09-10 00:00:00
abstract：:A series of 2-aryldopamine analogues were synthesized and evaluated for their effects on D1 and D2 dopamine receptors. The 2-phenyldopamine and 6-phenylbenzazepine analogues exhibited weak binding to both D1 and D2 receptors. The 9-(aminomethyl)fluorenes also exhibited weak D2 binding; however, 2,5,6-trihydroxy-9H-flu...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00160a018
更新日期：1986-10-01 00:00:00
