|
Inhibitory activity against adenosine uptake through P2 adenosine transporter of blood stream Trypanosoma brucei trypomastigotes at the concentration 100 ug/mL
|
Trypanosoma brucei
|
99.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : An approach to use an unusual adenosine transporter to selectively deliver polyamine analogues to trypanosomes.
Year : 1998
Volume : 8
Issue : 7
First Page : 811
Last Page : 816
Authors : Tye CK, Kasinathan G, Barrett MP, Brun R, Doyle VE, Fairlamb AH, Weaver R, Gilbert IH.
Abstract : In this paper we describe an approach to selectively deliver compounds to trypanosomes using an adenosine transporter which is unique to the trypanosome. Various polyamine analogues have been attached to known substrates of this adenosine transporter. The compounds prepared interact specifically with the adenosine transporter, some with a similar efficiency to berenil, a known substrate.
|
Inhibitory activity against adenosine uptake through P2 adenosine transporter of blood stream Trypanosoma brucei trypomastigotes at the concentration 10 ug/mL
|
Trypanosoma brucei
|
89.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : An approach to use an unusual adenosine transporter to selectively deliver polyamine analogues to trypanosomes.
Year : 1998
Volume : 8
Issue : 7
First Page : 811
Last Page : 816
Authors : Tye CK, Kasinathan G, Barrett MP, Brun R, Doyle VE, Fairlamb AH, Weaver R, Gilbert IH.
Abstract : In this paper we describe an approach to selectively deliver compounds to trypanosomes using an adenosine transporter which is unique to the trypanosome. Various polyamine analogues have been attached to known substrates of this adenosine transporter. The compounds prepared interact specifically with the adenosine transporter, some with a similar efficiency to berenil, a known substrate.
|
Inhibitory activity against adenosine uptake through P2 adenosine transporter of blood stream Trypanosoma brucei trypomastigotes at the concentration 1 ug/mL
|
Trypanosoma brucei
|
88.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : An approach to use an unusual adenosine transporter to selectively deliver polyamine analogues to trypanosomes.
Year : 1998
Volume : 8
Issue : 7
First Page : 811
Last Page : 816
Authors : Tye CK, Kasinathan G, Barrett MP, Brun R, Doyle VE, Fairlamb AH, Weaver R, Gilbert IH.
Abstract : In this paper we describe an approach to selectively deliver compounds to trypanosomes using an adenosine transporter which is unique to the trypanosome. Various polyamine analogues have been attached to known substrates of this adenosine transporter. The compounds prepared interact specifically with the adenosine transporter, some with a similar efficiency to berenil, a known substrate.
|
Inhibition of human Protein kinase C alpha
|
Homo sapiens
|
6.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors.
Year : 2005
Volume : 48
Issue : 3
First Page : 710
Last Page : 722
Authors : Laufer SA, Domeyer DM, Scior TR, Albrecht W, Hauser DR.
Abstract : On the basis of ATP adenine, a series of adenine and purine derivatives was prepared and tested for their ability to inhibit a spectrum of disease-related kinases. There has been scant research investigating the potential of cosubstrate derived kinase inhibitors for other kinases than CDKs. Our inhibitor design combined the purine system from the original cosubstrate ATP and phenyl moieties in order to explore possible interactions with the different regions of the ATP binding site in several disease-related protein kinases. There have been a number of hits for the assayed substances, which led us to conclude that the spectrum of compounds may prove to be a valuable tool kit for the evaluation of bonding and selectivity patterns for a wide variety of kinases.
|
Inhibition of human cAMP-dependent protein kinase (PKA)
|
Homo sapiens
|
14.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors.
Year : 2005
Volume : 48
Issue : 3
First Page : 710
Last Page : 722
Authors : Laufer SA, Domeyer DM, Scior TR, Albrecht W, Hauser DR.
Abstract : On the basis of ATP adenine, a series of adenine and purine derivatives was prepared and tested for their ability to inhibit a spectrum of disease-related kinases. There has been scant research investigating the potential of cosubstrate derived kinase inhibitors for other kinases than CDKs. Our inhibitor design combined the purine system from the original cosubstrate ATP and phenyl moieties in order to explore possible interactions with the different regions of the ATP binding site in several disease-related protein kinases. There have been a number of hits for the assayed substances, which led us to conclude that the spectrum of compounds may prove to be a valuable tool kit for the evaluation of bonding and selectivity patterns for a wide variety of kinases.
|
Inhibition of human Protein kinase B alpha at 30 uM
|
Homo sapiens
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors.
Year : 2005
Volume : 48
Issue : 3
First Page : 710
Last Page : 722
Authors : Laufer SA, Domeyer DM, Scior TR, Albrecht W, Hauser DR.
Abstract : On the basis of ATP adenine, a series of adenine and purine derivatives was prepared and tested for their ability to inhibit a spectrum of disease-related kinases. There has been scant research investigating the potential of cosubstrate derived kinase inhibitors for other kinases than CDKs. Our inhibitor design combined the purine system from the original cosubstrate ATP and phenyl moieties in order to explore possible interactions with the different regions of the ATP binding site in several disease-related protein kinases. There have been a number of hits for the assayed substances, which led us to conclude that the spectrum of compounds may prove to be a valuable tool kit for the evaluation of bonding and selectivity patterns for a wide variety of kinases.
|
Inhibition of rat c-Jun N-terminal kinase-3 at 30 uM
|
Rattus norvegicus
|
10.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors.
Year : 2005
Volume : 48
Issue : 3
First Page : 710
Last Page : 722
Authors : Laufer SA, Domeyer DM, Scior TR, Albrecht W, Hauser DR.
Abstract : On the basis of ATP adenine, a series of adenine and purine derivatives was prepared and tested for their ability to inhibit a spectrum of disease-related kinases. There has been scant research investigating the potential of cosubstrate derived kinase inhibitors for other kinases than CDKs. Our inhibitor design combined the purine system from the original cosubstrate ATP and phenyl moieties in order to explore possible interactions with the different regions of the ATP binding site in several disease-related protein kinases. There have been a number of hits for the assayed substances, which led us to conclude that the spectrum of compounds may prove to be a valuable tool kit for the evaluation of bonding and selectivity patterns for a wide variety of kinases.
|
Inhibition of human Glycogen synthase kinase-3 beta at 30 uM
|
Homo sapiens
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors.
Year : 2005
Volume : 48
Issue : 3
First Page : 710
Last Page : 722
Authors : Laufer SA, Domeyer DM, Scior TR, Albrecht W, Hauser DR.
Abstract : On the basis of ATP adenine, a series of adenine and purine derivatives was prepared and tested for their ability to inhibit a spectrum of disease-related kinases. There has been scant research investigating the potential of cosubstrate derived kinase inhibitors for other kinases than CDKs. Our inhibitor design combined the purine system from the original cosubstrate ATP and phenyl moieties in order to explore possible interactions with the different regions of the ATP binding site in several disease-related protein kinases. There have been a number of hits for the assayed substances, which led us to conclude that the spectrum of compounds may prove to be a valuable tool kit for the evaluation of bonding and selectivity patterns for a wide variety of kinases.
|
Inhibition of human Rho-dependent protein kinase-II at 30 uM
|
Homo sapiens
|
28.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors.
Year : 2005
Volume : 48
Issue : 3
First Page : 710
Last Page : 722
Authors : Laufer SA, Domeyer DM, Scior TR, Albrecht W, Hauser DR.
Abstract : On the basis of ATP adenine, a series of adenine and purine derivatives was prepared and tested for their ability to inhibit a spectrum of disease-related kinases. There has been scant research investigating the potential of cosubstrate derived kinase inhibitors for other kinases than CDKs. Our inhibitor design combined the purine system from the original cosubstrate ATP and phenyl moieties in order to explore possible interactions with the different regions of the ATP binding site in several disease-related protein kinases. There have been a number of hits for the assayed substances, which led us to conclude that the spectrum of compounds may prove to be a valuable tool kit for the evaluation of bonding and selectivity patterns for a wide variety of kinases.
|
Inhibition of human c-Jun N-terminal kinase-1 alpha-1 at 30 uM
|
Homo sapiens
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors.
Year : 2005
Volume : 48
Issue : 3
First Page : 710
Last Page : 722
Authors : Laufer SA, Domeyer DM, Scior TR, Albrecht W, Hauser DR.
Abstract : On the basis of ATP adenine, a series of adenine and purine derivatives was prepared and tested for their ability to inhibit a spectrum of disease-related kinases. There has been scant research investigating the potential of cosubstrate derived kinase inhibitors for other kinases than CDKs. Our inhibitor design combined the purine system from the original cosubstrate ATP and phenyl moieties in order to explore possible interactions with the different regions of the ATP binding site in several disease-related protein kinases. There have been a number of hits for the assayed substances, which led us to conclude that the spectrum of compounds may prove to be a valuable tool kit for the evaluation of bonding and selectivity patterns for a wide variety of kinases.
|
Inhibition of human c-Jun N-terminal kinase-2 alpha-2 at 30 uM
|
Homo sapiens
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors.
Year : 2005
Volume : 48
Issue : 3
First Page : 710
Last Page : 722
Authors : Laufer SA, Domeyer DM, Scior TR, Albrecht W, Hauser DR.
Abstract : On the basis of ATP adenine, a series of adenine and purine derivatives was prepared and tested for their ability to inhibit a spectrum of disease-related kinases. There has been scant research investigating the potential of cosubstrate derived kinase inhibitors for other kinases than CDKs. Our inhibitor design combined the purine system from the original cosubstrate ATP and phenyl moieties in order to explore possible interactions with the different regions of the ATP binding site in several disease-related protein kinases. There have been a number of hits for the assayed substances, which led us to conclude that the spectrum of compounds may prove to be a valuable tool kit for the evaluation of bonding and selectivity patterns for a wide variety of kinases.
|
Inhibition of human Mitogen-activated protein kinase 1 at 30 uM
|
Homo sapiens
|
3.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors.
Year : 2005
Volume : 48
Issue : 3
First Page : 710
Last Page : 722
Authors : Laufer SA, Domeyer DM, Scior TR, Albrecht W, Hauser DR.
Abstract : On the basis of ATP adenine, a series of adenine and purine derivatives was prepared and tested for their ability to inhibit a spectrum of disease-related kinases. There has been scant research investigating the potential of cosubstrate derived kinase inhibitors for other kinases than CDKs. Our inhibitor design combined the purine system from the original cosubstrate ATP and phenyl moieties in order to explore possible interactions with the different regions of the ATP binding site in several disease-related protein kinases. There have been a number of hits for the assayed substances, which led us to conclude that the spectrum of compounds may prove to be a valuable tool kit for the evaluation of bonding and selectivity patterns for a wide variety of kinases.
|
Inhibition of human Mitogen-activated protein kinase 2 at 30 uM
|
Homo sapiens
|
17.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors.
Year : 2005
Volume : 48
Issue : 3
First Page : 710
Last Page : 722
Authors : Laufer SA, Domeyer DM, Scior TR, Albrecht W, Hauser DR.
Abstract : On the basis of ATP adenine, a series of adenine and purine derivatives was prepared and tested for their ability to inhibit a spectrum of disease-related kinases. There has been scant research investigating the potential of cosubstrate derived kinase inhibitors for other kinases than CDKs. Our inhibitor design combined the purine system from the original cosubstrate ATP and phenyl moieties in order to explore possible interactions with the different regions of the ATP binding site in several disease-related protein kinases. There have been a number of hits for the assayed substances, which led us to conclude that the spectrum of compounds may prove to be a valuable tool kit for the evaluation of bonding and selectivity patterns for a wide variety of kinases.
|
Inhibition of human lymphocyte protein tyrosine kinase Lck at 30 uM
|
Homo sapiens
|
19.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors.
Year : 2005
Volume : 48
Issue : 3
First Page : 710
Last Page : 722
Authors : Laufer SA, Domeyer DM, Scior TR, Albrecht W, Hauser DR.
Abstract : On the basis of ATP adenine, a series of adenine and purine derivatives was prepared and tested for their ability to inhibit a spectrum of disease-related kinases. There has been scant research investigating the potential of cosubstrate derived kinase inhibitors for other kinases than CDKs. Our inhibitor design combined the purine system from the original cosubstrate ATP and phenyl moieties in order to explore possible interactions with the different regions of the ATP binding site in several disease-related protein kinases. There have been a number of hits for the assayed substances, which led us to conclude that the spectrum of compounds may prove to be a valuable tool kit for the evaluation of bonding and selectivity patterns for a wide variety of kinases.
|
Inhibition of human stress-activated protein kinase-2 alpha (p38 MAP-kinase) at 30 uM
|
Homo sapiens
|
7.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors.
Year : 2005
Volume : 48
Issue : 3
First Page : 710
Last Page : 722
Authors : Laufer SA, Domeyer DM, Scior TR, Albrecht W, Hauser DR.
Abstract : On the basis of ATP adenine, a series of adenine and purine derivatives was prepared and tested for their ability to inhibit a spectrum of disease-related kinases. There has been scant research investigating the potential of cosubstrate derived kinase inhibitors for other kinases than CDKs. Our inhibitor design combined the purine system from the original cosubstrate ATP and phenyl moieties in order to explore possible interactions with the different regions of the ATP binding site in several disease-related protein kinases. There have been a number of hits for the assayed substances, which led us to conclude that the spectrum of compounds may prove to be a valuable tool kit for the evaluation of bonding and selectivity patterns for a wide variety of kinases.
|
Inhibition of human Mitogen activated protein kinase kinase 1 (MEK1) at 30 uM
|
Homo sapiens
|
9.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors.
Year : 2005
Volume : 48
Issue : 3
First Page : 710
Last Page : 722
Authors : Laufer SA, Domeyer DM, Scior TR, Albrecht W, Hauser DR.
Abstract : On the basis of ATP adenine, a series of adenine and purine derivatives was prepared and tested for their ability to inhibit a spectrum of disease-related kinases. There has been scant research investigating the potential of cosubstrate derived kinase inhibitors for other kinases than CDKs. Our inhibitor design combined the purine system from the original cosubstrate ATP and phenyl moieties in order to explore possible interactions with the different regions of the ATP binding site in several disease-related protein kinases. There have been a number of hits for the assayed substances, which led us to conclude that the spectrum of compounds may prove to be a valuable tool kit for the evaluation of bonding and selectivity patterns for a wide variety of kinases.
|
Inhibition of human RAF proto-oncogene serine/threonine-protein kinase at 30 uM
|
Homo sapiens
|
14.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors.
Year : 2005
Volume : 48
Issue : 3
First Page : 710
Last Page : 722
Authors : Laufer SA, Domeyer DM, Scior TR, Albrecht W, Hauser DR.
Abstract : On the basis of ATP adenine, a series of adenine and purine derivatives was prepared and tested for their ability to inhibit a spectrum of disease-related kinases. There has been scant research investigating the potential of cosubstrate derived kinase inhibitors for other kinases than CDKs. Our inhibitor design combined the purine system from the original cosubstrate ATP and phenyl moieties in order to explore possible interactions with the different regions of the ATP binding site in several disease-related protein kinases. There have been a number of hits for the assayed substances, which led us to conclude that the spectrum of compounds may prove to be a valuable tool kit for the evaluation of bonding and selectivity patterns for a wide variety of kinases.
|
Inhibition of rat Calcium/calmodulin-dependent protein kinase type II at 30 uM
|
None
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors.
Year : 2005
Volume : 48
Issue : 3
First Page : 710
Last Page : 722
Authors : Laufer SA, Domeyer DM, Scior TR, Albrecht W, Hauser DR.
Abstract : On the basis of ATP adenine, a series of adenine and purine derivatives was prepared and tested for their ability to inhibit a spectrum of disease-related kinases. There has been scant research investigating the potential of cosubstrate derived kinase inhibitors for other kinases than CDKs. Our inhibitor design combined the purine system from the original cosubstrate ATP and phenyl moieties in order to explore possible interactions with the different regions of the ATP binding site in several disease-related protein kinases. There have been a number of hits for the assayed substances, which led us to conclude that the spectrum of compounds may prove to be a valuable tool kit for the evaluation of bonding and selectivity patterns for a wide variety of kinases.
|
Inhibition of human xanthine oxidase at 30 uM
|
Homo sapiens
|
61.3
%
|
|
Journal : Bioorg. Med. Chem.
Title : The screening and characterization of 6-aminopurine-based xanthine oxidase inhibitors.
Year : 2007
Volume : 15
Issue : 10
First Page : 3450
Last Page : 3456
Authors : Hsieh JF, Wu SH, Yang YL, Choong KF, Chen ST.
Abstract : Xanthine oxidase (XO) is a key enzyme which can catalyze xanthine to uric acid causing hyperuricemia in humans. By using the fractionation technique and inhibitory activity assay, an active compound that prevents XO from reacting with xanthine was isolated from wheat leaf. It was identified by the Mass and NMR as 6-aminopurine (adenine). A structure-activity study based on 6-aminopurine was conducted. The inhibition of XO activity by 6-aminopurine (IC(50)=10.89+/-0.13 microM) and its analogues was compared with that by allopurinol (IC(50)=7.82+/-0.12 microM). Among these analogues, 2-chloro-6(methylamino)purine (IC(50)=10.19+/-0.10 microM) and 4-aminopyrazolo[3,4-d] pyrimidine (IC(50)=30.26+/-0.23 microM) were found to be potent inhibitors of XO. Kinetics study showed that 2-chloro-6(methylamino)purine is non-competitive, while 4-aminopyrazolo[3,4-d]pyrimidine is competitive against XO.
|
Inhibition of phosphatidylinositol 4-kinase in human A431 cell membrane by liquid scintillation counting
|
Homo sapiens
|
100.0
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Isolation and structure determination of novel phosphatidylinositol kinase inhibitors, echiguanines A and B, from Streptomyces sp.
Year : 1991
Volume : 54
Issue : 5
First Page : 1321
Last Page : 1325
Authors : Nishioka H, Sawa T, Nakamura H, Iinuma H, Ikeda D, Sawa R, Naganawa H, Hayashi C, Hamada M, Takeuchi T.
Abstract : In the course of a screening program for phosphatidylinositol kinase inhibitors, we discovered novel inhibitors, echiguanines A and B, from the culture broth of a Streptomyces strain MI698-50F1 (FERMP-11563). The structures of echiguanines A and B were revealed to be N-(2-amidinoethyl)-2-amino-4-hydroxy-7H-pyrrolo[2,3- d]pyrimidine-5-carboxamide and N-(3-aminopropyl)-2-amino-4-hydroxy-7H-pyrrolo[2,3-d]pyrimidine- 5-carboxamide, respectively, by nmr spectroscopy and X-ray crystallography. Echiguanines A and B inhibited phosphatidylinositol kinase of the A431 cell membrane with IC50's of 0.04 microgram/ml and 0.11 micrograms/ml, respectively. Echiguanine A is the most potent inhibitor of phosphatidylinositol kinase so far discovered.
|
Displacement of [3H]adenine from adenine 1 receptor in rat brain cortical membrane by liquid scintillation counting
|
Rattus norvegicus
|
29.2
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships of adenine and deazaadenine derivatives as ligands for adenine receptors, a new purinergic receptor family.
Year : 2009
Volume : 52
Issue : 19
First Page : 5974
Last Page : 5989
Authors : Borrmann T, Abdelrahman A, Volpini R, Lambertucci C, Alksnis E, Gorzalka S, Knospe M, Schiedel AC, Cristalli G, Müller CE.
Abstract : Adenine derivatives bearing substituents in the 2-, N(6)-, 7-, 8-, and/or 9-position and a series of deazapurines were synthesized and investigated in [(3)H]adenine binding studies at the adenine receptor in rat brain cortical membrane preparations (rAde1R). Steep structure-activity relationships were observed. Substitution in the 8-position (amino, dimethylamino, piperidinyl, piperazinyl) or in the 9-position (2-morpholinoethyl) with basic residues or introduction of polar substituents at the 6-amino function (hydroxy, amino, acetyl) represented the best modifications. Functional evaluation of selected adenine derivatives in adenylate cyclase assays at 1321N1 astrocytoma cells stably expressing the rAde1R showed that all compounds investigated were agonists or partial agonists. A subset of compounds was additionally investigated in binding studies at human embryonic kidney (HEK293) cells, which also express a high-affinity adenine binding site. Structure-affinity relationships at the human cell line were similar to those at the rAde1R, but not identical. In particular, N(6)-acetyladenine (25, K(i) rat: 2.85 microM; K(i) human: 0.515 microM) and 8-aminoadenine (33, K(i) rat: 6.51 microM; K(i) human: 0.0341 microM) were much more potent at the human as compared to the rat binding site. The new AdeR ligands may serve as lead structures and contribute to the elucidation of the functions of the adenine receptor family.
|
Displacement of [3H]adenine from adenine 1 receptor in HEK293 cells by liquid scintillation counting
|
Homo sapiens
|
47.1
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships of adenine and deazaadenine derivatives as ligands for adenine receptors, a new purinergic receptor family.
Year : 2009
Volume : 52
Issue : 19
First Page : 5974
Last Page : 5989
Authors : Borrmann T, Abdelrahman A, Volpini R, Lambertucci C, Alksnis E, Gorzalka S, Knospe M, Schiedel AC, Cristalli G, Müller CE.
Abstract : Adenine derivatives bearing substituents in the 2-, N(6)-, 7-, 8-, and/or 9-position and a series of deazapurines were synthesized and investigated in [(3)H]adenine binding studies at the adenine receptor in rat brain cortical membrane preparations (rAde1R). Steep structure-activity relationships were observed. Substitution in the 8-position (amino, dimethylamino, piperidinyl, piperazinyl) or in the 9-position (2-morpholinoethyl) with basic residues or introduction of polar substituents at the 6-amino function (hydroxy, amino, acetyl) represented the best modifications. Functional evaluation of selected adenine derivatives in adenylate cyclase assays at 1321N1 astrocytoma cells stably expressing the rAde1R showed that all compounds investigated were agonists or partial agonists. A subset of compounds was additionally investigated in binding studies at human embryonic kidney (HEK293) cells, which also express a high-affinity adenine binding site. Structure-affinity relationships at the human cell line were similar to those at the rAde1R, but not identical. In particular, N(6)-acetyladenine (25, K(i) rat: 2.85 microM; K(i) human: 0.515 microM) and 8-aminoadenine (33, K(i) rat: 6.51 microM; K(i) human: 0.0341 microM) were much more potent at the human as compared to the rat binding site. The new AdeR ligands may serve as lead structures and contribute to the elucidation of the functions of the adenine receptor family.
|
Agonist activity at rat adenine 1 receptor expressed in human 1321N1 cells assessed as inhibition of isoproterenol-induced [3H]cAMP formation at 1 uM by scintillation counting
|
Rattus norvegicus
|
35.0
%
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships of adenine and deazaadenine derivatives as ligands for adenine receptors, a new purinergic receptor family.
Year : 2009
Volume : 52
Issue : 19
First Page : 5974
Last Page : 5989
Authors : Borrmann T, Abdelrahman A, Volpini R, Lambertucci C, Alksnis E, Gorzalka S, Knospe M, Schiedel AC, Cristalli G, Müller CE.
Abstract : Adenine derivatives bearing substituents in the 2-, N(6)-, 7-, 8-, and/or 9-position and a series of deazapurines were synthesized and investigated in [(3)H]adenine binding studies at the adenine receptor in rat brain cortical membrane preparations (rAde1R). Steep structure-activity relationships were observed. Substitution in the 8-position (amino, dimethylamino, piperidinyl, piperazinyl) or in the 9-position (2-morpholinoethyl) with basic residues or introduction of polar substituents at the 6-amino function (hydroxy, amino, acetyl) represented the best modifications. Functional evaluation of selected adenine derivatives in adenylate cyclase assays at 1321N1 astrocytoma cells stably expressing the rAde1R showed that all compounds investigated were agonists or partial agonists. A subset of compounds was additionally investigated in binding studies at human embryonic kidney (HEK293) cells, which also express a high-affinity adenine binding site. Structure-affinity relationships at the human cell line were similar to those at the rAde1R, but not identical. In particular, N(6)-acetyladenine (25, K(i) rat: 2.85 microM; K(i) human: 0.515 microM) and 8-aminoadenine (33, K(i) rat: 6.51 microM; K(i) human: 0.0341 microM) were much more potent at the human as compared to the rat binding site. The new AdeR ligands may serve as lead structures and contribute to the elucidation of the functions of the adenine receptor family.
|
Inhibition of mushroom tyrosinase at 1 mM after 10 mins
|
Agaricus bisporus
|
11.0
%
|
|
Journal : J. Med. Chem.
Title : Identifying chelators for metalloprotein inhibitors using a fragment-based approach.
Year : 2011
Volume : 54
Issue : 2
First Page : 591
Last Page : 602
Authors : Jacobsen JA, Fullagar JL, Miller MT, Cohen SM.
Abstract : Fragment-based lead design (FBLD) has been used to identify new metal-binding groups for metalloenzyme inhibitors. When screened at 1 mM, a chelator fragment library (CFL-1.1) of 96 compounds produced hit rates ranging from 29% to 43% for five matrix metalloproteases (MMPs), 24% for anthrax lethal factor (LF), 49% for 5-lipoxygenase (5-LO), and 60% for tyrosinase (TY). The ligand efficiencies (LE) of the fragment hits are excellent, in the range of 0.4-0.8 kcal/mol. The MMP enzymes all generally elicit the same chelators as hits from CFL-1.1; however, the chelator fragments that inhibit structurally unrelated metalloenzymes (LF, 5-LO, TY) vary considerably. To develop more advanced hits, one hit from CFL-1.1, 8-hydroxyquinoline, was elaborated at four different positions around the ring system to generate new fragments. 8-Hydroxyquinoline fragments substituted at either the 5- or 7-positions gave potent hits against MMP-2, with IC(50) values in the low micromolar range. The 8-hydroxyquinoline represents a promising new chelator scaffold for the development of MMP inhibitors that was discovered by use of a metalloprotein-focused chelator fragment library.
|
Inhibition of human recombinant 5-lipoxygenase at 1 mM after 10 mins by fluorescence assay
|
Homo sapiens
|
9.0
%
|
|
Journal : J. Med. Chem.
Title : Identifying chelators for metalloprotein inhibitors using a fragment-based approach.
Year : 2011
Volume : 54
Issue : 2
First Page : 591
Last Page : 602
Authors : Jacobsen JA, Fullagar JL, Miller MT, Cohen SM.
Abstract : Fragment-based lead design (FBLD) has been used to identify new metal-binding groups for metalloenzyme inhibitors. When screened at 1 mM, a chelator fragment library (CFL-1.1) of 96 compounds produced hit rates ranging from 29% to 43% for five matrix metalloproteases (MMPs), 24% for anthrax lethal factor (LF), 49% for 5-lipoxygenase (5-LO), and 60% for tyrosinase (TY). The ligand efficiencies (LE) of the fragment hits are excellent, in the range of 0.4-0.8 kcal/mol. The MMP enzymes all generally elicit the same chelators as hits from CFL-1.1; however, the chelator fragments that inhibit structurally unrelated metalloenzymes (LF, 5-LO, TY) vary considerably. To develop more advanced hits, one hit from CFL-1.1, 8-hydroxyquinoline, was elaborated at four different positions around the ring system to generate new fragments. 8-Hydroxyquinoline fragments substituted at either the 5- or 7-positions gave potent hits against MMP-2, with IC(50) values in the low micromolar range. The 8-hydroxyquinoline represents a promising new chelator scaffold for the development of MMP inhibitors that was discovered by use of a metalloprotein-focused chelator fragment library.
|
Inhibition of recombinant anthrax lethal factor at 1 mM after 30 mins by fluorescence assay
|
Bacillus anthracis
|
16.0
%
|
|
Journal : J. Med. Chem.
Title : Identifying chelators for metalloprotein inhibitors using a fragment-based approach.
Year : 2011
Volume : 54
Issue : 2
First Page : 591
Last Page : 602
Authors : Jacobsen JA, Fullagar JL, Miller MT, Cohen SM.
Abstract : Fragment-based lead design (FBLD) has been used to identify new metal-binding groups for metalloenzyme inhibitors. When screened at 1 mM, a chelator fragment library (CFL-1.1) of 96 compounds produced hit rates ranging from 29% to 43% for five matrix metalloproteases (MMPs), 24% for anthrax lethal factor (LF), 49% for 5-lipoxygenase (5-LO), and 60% for tyrosinase (TY). The ligand efficiencies (LE) of the fragment hits are excellent, in the range of 0.4-0.8 kcal/mol. The MMP enzymes all generally elicit the same chelators as hits from CFL-1.1; however, the chelator fragments that inhibit structurally unrelated metalloenzymes (LF, 5-LO, TY) vary considerably. To develop more advanced hits, one hit from CFL-1.1, 8-hydroxyquinoline, was elaborated at four different positions around the ring system to generate new fragments. 8-Hydroxyquinoline fragments substituted at either the 5- or 7-positions gave potent hits against MMP-2, with IC(50) values in the low micromolar range. The 8-hydroxyquinoline represents a promising new chelator scaffold for the development of MMP inhibitors that was discovered by use of a metalloprotein-focused chelator fragment library.
|
Inhibition of human recombinant MMP1 at 1 mM after 30 mins
|
Homo sapiens
|
17.0
%
|
|
Journal : J. Med. Chem.
Title : Identifying chelators for metalloprotein inhibitors using a fragment-based approach.
Year : 2011
Volume : 54
Issue : 2
First Page : 591
Last Page : 602
Authors : Jacobsen JA, Fullagar JL, Miller MT, Cohen SM.
Abstract : Fragment-based lead design (FBLD) has been used to identify new metal-binding groups for metalloenzyme inhibitors. When screened at 1 mM, a chelator fragment library (CFL-1.1) of 96 compounds produced hit rates ranging from 29% to 43% for five matrix metalloproteases (MMPs), 24% for anthrax lethal factor (LF), 49% for 5-lipoxygenase (5-LO), and 60% for tyrosinase (TY). The ligand efficiencies (LE) of the fragment hits are excellent, in the range of 0.4-0.8 kcal/mol. The MMP enzymes all generally elicit the same chelators as hits from CFL-1.1; however, the chelator fragments that inhibit structurally unrelated metalloenzymes (LF, 5-LO, TY) vary considerably. To develop more advanced hits, one hit from CFL-1.1, 8-hydroxyquinoline, was elaborated at four different positions around the ring system to generate new fragments. 8-Hydroxyquinoline fragments substituted at either the 5- or 7-positions gave potent hits against MMP-2, with IC(50) values in the low micromolar range. The 8-hydroxyquinoline represents a promising new chelator scaffold for the development of MMP inhibitors that was discovered by use of a metalloprotein-focused chelator fragment library.
|
Inhibition of human recombinant MMP2 at 1 mM after 30 mins
|
Homo sapiens
|
-1.0
%
|
|
Journal : J. Med. Chem.
Title : Identifying chelators for metalloprotein inhibitors using a fragment-based approach.
Year : 2011
Volume : 54
Issue : 2
First Page : 591
Last Page : 602
Authors : Jacobsen JA, Fullagar JL, Miller MT, Cohen SM.
Abstract : Fragment-based lead design (FBLD) has been used to identify new metal-binding groups for metalloenzyme inhibitors. When screened at 1 mM, a chelator fragment library (CFL-1.1) of 96 compounds produced hit rates ranging from 29% to 43% for five matrix metalloproteases (MMPs), 24% for anthrax lethal factor (LF), 49% for 5-lipoxygenase (5-LO), and 60% for tyrosinase (TY). The ligand efficiencies (LE) of the fragment hits are excellent, in the range of 0.4-0.8 kcal/mol. The MMP enzymes all generally elicit the same chelators as hits from CFL-1.1; however, the chelator fragments that inhibit structurally unrelated metalloenzymes (LF, 5-LO, TY) vary considerably. To develop more advanced hits, one hit from CFL-1.1, 8-hydroxyquinoline, was elaborated at four different positions around the ring system to generate new fragments. 8-Hydroxyquinoline fragments substituted at either the 5- or 7-positions gave potent hits against MMP-2, with IC(50) values in the low micromolar range. The 8-hydroxyquinoline represents a promising new chelator scaffold for the development of MMP inhibitors that was discovered by use of a metalloprotein-focused chelator fragment library.
|
Inhibition of human recombinant MMP3 at 1 mM after 30 mins
|
Homo sapiens
|
10.0
%
|
|
Journal : J. Med. Chem.
Title : Identifying chelators for metalloprotein inhibitors using a fragment-based approach.
Year : 2011
Volume : 54
Issue : 2
First Page : 591
Last Page : 602
Authors : Jacobsen JA, Fullagar JL, Miller MT, Cohen SM.
Abstract : Fragment-based lead design (FBLD) has been used to identify new metal-binding groups for metalloenzyme inhibitors. When screened at 1 mM, a chelator fragment library (CFL-1.1) of 96 compounds produced hit rates ranging from 29% to 43% for five matrix metalloproteases (MMPs), 24% for anthrax lethal factor (LF), 49% for 5-lipoxygenase (5-LO), and 60% for tyrosinase (TY). The ligand efficiencies (LE) of the fragment hits are excellent, in the range of 0.4-0.8 kcal/mol. The MMP enzymes all generally elicit the same chelators as hits from CFL-1.1; however, the chelator fragments that inhibit structurally unrelated metalloenzymes (LF, 5-LO, TY) vary considerably. To develop more advanced hits, one hit from CFL-1.1, 8-hydroxyquinoline, was elaborated at four different positions around the ring system to generate new fragments. 8-Hydroxyquinoline fragments substituted at either the 5- or 7-positions gave potent hits against MMP-2, with IC(50) values in the low micromolar range. The 8-hydroxyquinoline represents a promising new chelator scaffold for the development of MMP inhibitors that was discovered by use of a metalloprotein-focused chelator fragment library.
|
Inhibition of human recombinant MMP8 at 1 mM after 30 mins
|
Homo sapiens
|
9.0
%
|
|
Journal : J. Med. Chem.
Title : Identifying chelators for metalloprotein inhibitors using a fragment-based approach.
Year : 2011
Volume : 54
Issue : 2
First Page : 591
Last Page : 602
Authors : Jacobsen JA, Fullagar JL, Miller MT, Cohen SM.
Abstract : Fragment-based lead design (FBLD) has been used to identify new metal-binding groups for metalloenzyme inhibitors. When screened at 1 mM, a chelator fragment library (CFL-1.1) of 96 compounds produced hit rates ranging from 29% to 43% for five matrix metalloproteases (MMPs), 24% for anthrax lethal factor (LF), 49% for 5-lipoxygenase (5-LO), and 60% for tyrosinase (TY). The ligand efficiencies (LE) of the fragment hits are excellent, in the range of 0.4-0.8 kcal/mol. The MMP enzymes all generally elicit the same chelators as hits from CFL-1.1; however, the chelator fragments that inhibit structurally unrelated metalloenzymes (LF, 5-LO, TY) vary considerably. To develop more advanced hits, one hit from CFL-1.1, 8-hydroxyquinoline, was elaborated at four different positions around the ring system to generate new fragments. 8-Hydroxyquinoline fragments substituted at either the 5- or 7-positions gave potent hits against MMP-2, with IC(50) values in the low micromolar range. The 8-hydroxyquinoline represents a promising new chelator scaffold for the development of MMP inhibitors that was discovered by use of a metalloprotein-focused chelator fragment library.
|
Inhibition of human recombinant MMP9 at 1 mM after 30 mins
|
Homo sapiens
|
-3.0
%
|
|
Journal : J. Med. Chem.
Title : Identifying chelators for metalloprotein inhibitors using a fragment-based approach.
Year : 2011
Volume : 54
Issue : 2
First Page : 591
Last Page : 602
Authors : Jacobsen JA, Fullagar JL, Miller MT, Cohen SM.
Abstract : Fragment-based lead design (FBLD) has been used to identify new metal-binding groups for metalloenzyme inhibitors. When screened at 1 mM, a chelator fragment library (CFL-1.1) of 96 compounds produced hit rates ranging from 29% to 43% for five matrix metalloproteases (MMPs), 24% for anthrax lethal factor (LF), 49% for 5-lipoxygenase (5-LO), and 60% for tyrosinase (TY). The ligand efficiencies (LE) of the fragment hits are excellent, in the range of 0.4-0.8 kcal/mol. The MMP enzymes all generally elicit the same chelators as hits from CFL-1.1; however, the chelator fragments that inhibit structurally unrelated metalloenzymes (LF, 5-LO, TY) vary considerably. To develop more advanced hits, one hit from CFL-1.1, 8-hydroxyquinoline, was elaborated at four different positions around the ring system to generate new fragments. 8-Hydroxyquinoline fragments substituted at either the 5- or 7-positions gave potent hits against MMP-2, with IC(50) values in the low micromolar range. The 8-hydroxyquinoline represents a promising new chelator scaffold for the development of MMP inhibitors that was discovered by use of a metalloprotein-focused chelator fragment library.
|
Inhibition of mouse recombinant iNOS at 1 mM after 40 mins by colorimetric assay
|
Mus musculus
|
6.0
%
|
|
Journal : J. Med. Chem.
Title : Identifying chelators for metalloprotein inhibitors using a fragment-based approach.
Year : 2011
Volume : 54
Issue : 2
First Page : 591
Last Page : 602
Authors : Jacobsen JA, Fullagar JL, Miller MT, Cohen SM.
Abstract : Fragment-based lead design (FBLD) has been used to identify new metal-binding groups for metalloenzyme inhibitors. When screened at 1 mM, a chelator fragment library (CFL-1.1) of 96 compounds produced hit rates ranging from 29% to 43% for five matrix metalloproteases (MMPs), 24% for anthrax lethal factor (LF), 49% for 5-lipoxygenase (5-LO), and 60% for tyrosinase (TY). The ligand efficiencies (LE) of the fragment hits are excellent, in the range of 0.4-0.8 kcal/mol. The MMP enzymes all generally elicit the same chelators as hits from CFL-1.1; however, the chelator fragments that inhibit structurally unrelated metalloenzymes (LF, 5-LO, TY) vary considerably. To develop more advanced hits, one hit from CFL-1.1, 8-hydroxyquinoline, was elaborated at four different positions around the ring system to generate new fragments. 8-Hydroxyquinoline fragments substituted at either the 5- or 7-positions gave potent hits against MMP-2, with IC(50) values in the low micromolar range. The 8-hydroxyquinoline represents a promising new chelator scaffold for the development of MMP inhibitors that was discovered by use of a metalloprotein-focused chelator fragment library.
|
Inhibition of IKK-beta expressed in Escherichia coli or baculovirus-infected insect cells at 667 uM by TR-FRET assay
|
None
|
22.0
%
|
|
Journal : J. Med. Chem.
Title : Selectivity of kinase inhibitor fragments.
Year : 2011
Volume : 54
Issue : 14
First Page : 5131
Last Page : 5143
Authors : Bamborough P, Brown MJ, Christopher JA, Chung CW, Mellor GW.
Abstract : A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
|
Inhibition of PI3Kgamma expressed in Escherichia coli or baculovirus-infected insect cells at 667 uM by fluorescence polarization assay
|
None
|
66.0
%
|
|
Journal : J. Med. Chem.
Title : Selectivity of kinase inhibitor fragments.
Year : 2011
Volume : 54
Issue : 14
First Page : 5131
Last Page : 5143
Authors : Bamborough P, Brown MJ, Christopher JA, Chung CW, Mellor GW.
Abstract : A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
|
Inhibition of JNK1 expressed in Escherichia coli or baculovirus-infected insect cells at 667 uM by TR-FRET assay
|
None
|
33.0
%
|
|
Journal : J. Med. Chem.
Title : Selectivity of kinase inhibitor fragments.
Year : 2011
Volume : 54
Issue : 14
First Page : 5131
Last Page : 5143
Authors : Bamborough P, Brown MJ, Christopher JA, Chung CW, Mellor GW.
Abstract : A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
|
Inhibition of AKT1 expressed in Escherichia coli or baculovirus-infected insect cells using gamma-[33P]ATP at 400 uM by scintillation proximity assay
|
None
|
20.0
%
|
|
Journal : J. Med. Chem.
Title : Selectivity of kinase inhibitor fragments.
Year : 2011
Volume : 54
Issue : 14
First Page : 5131
Last Page : 5143
Authors : Bamborough P, Brown MJ, Christopher JA, Chung CW, Mellor GW.
Abstract : A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
|
Inhibition of AKT2 expressed in Escherichia coli or baculovirus-infected insect cells using gamma-[33P]ATP at 400 uM by scintillation proximity assay
|
None
|
7.0
%
|
|
Journal : J. Med. Chem.
Title : Selectivity of kinase inhibitor fragments.
Year : 2011
Volume : 54
Issue : 14
First Page : 5131
Last Page : 5143
Authors : Bamborough P, Brown MJ, Christopher JA, Chung CW, Mellor GW.
Abstract : A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
|
Inhibition of ASK1 expressed in Escherichia coli or baculovirus-infected insect cells at 667 uM by IMAP assay
|
None
|
88.0
%
|
|
Journal : J. Med. Chem.
Title : Selectivity of kinase inhibitor fragments.
Year : 2011
Volume : 54
Issue : 14
First Page : 5131
Last Page : 5143
Authors : Bamborough P, Brown MJ, Christopher JA, Chung CW, Mellor GW.
Abstract : A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
|
Inhibition of AurA expressed in Escherichia coli or baculovirus-infected insect cells at 400 uM by IMAP assay
|
None
|
90.0
%
|
|
Journal : J. Med. Chem.
Title : Selectivity of kinase inhibitor fragments.
Year : 2011
Volume : 54
Issue : 14
First Page : 5131
Last Page : 5143
Authors : Bamborough P, Brown MJ, Christopher JA, Chung CW, Mellor GW.
Abstract : A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
|
Inhibition of AurB expressed in Escherichia coli or baculovirus-infected insect cells at 400 uM by IMAP assay
|
None
|
99.0
%
|
|
Journal : J. Med. Chem.
Title : Selectivity of kinase inhibitor fragments.
Year : 2011
Volume : 54
Issue : 14
First Page : 5131
Last Page : 5143
Authors : Bamborough P, Brown MJ, Christopher JA, Chung CW, Mellor GW.
Abstract : A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
|
Inhibition of B-Raf expressed in Escherichia coli or baculovirus-infected insect cells using ATP as substrate at 400 uM by fluorescence polarization assay
|
None
|
63.0
%
|
|
Journal : J. Med. Chem.
Title : Selectivity of kinase inhibitor fragments.
Year : 2011
Volume : 54
Issue : 14
First Page : 5131
Last Page : 5143
Authors : Bamborough P, Brown MJ, Christopher JA, Chung CW, Mellor GW.
Abstract : A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
|
Inhibition of EGFR expressed in Escherichia coli or baculovirus-infected insect cells at 400 uM by TR-FRET assay
|
None
|
11.0
%
|
|
Journal : J. Med. Chem.
Title : Selectivity of kinase inhibitor fragments.
Year : 2011
Volume : 54
Issue : 14
First Page : 5131
Last Page : 5143
Authors : Bamborough P, Brown MJ, Christopher JA, Chung CW, Mellor GW.
Abstract : A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
|
Inhibition of FES expressed in Escherichia coli or baculovirus-infected insect cells using ATP as substrate at 400 uM by fluorescence polarization assay
|
None
|
20.0
%
|
|
Journal : J. Med. Chem.
Title : Selectivity of kinase inhibitor fragments.
Year : 2011
Volume : 54
Issue : 14
First Page : 5131
Last Page : 5143
Authors : Bamborough P, Brown MJ, Christopher JA, Chung CW, Mellor GW.
Abstract : A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
|
Inhibition of ErbB2 expressed in Escherichia coli or baculovirus-infected insect cells at 400 uM by TR-FRET assay
|
None
|
3.0
%
|
|
Journal : J. Med. Chem.
Title : Selectivity of kinase inhibitor fragments.
Year : 2011
Volume : 54
Issue : 14
First Page : 5131
Last Page : 5143
Authors : Bamborough P, Brown MJ, Christopher JA, Chung CW, Mellor GW.
Abstract : A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
|
Inhibition of ErbB4 expressed in Escherichia coli or baculovirus-infected insect cells at 400 to 667 uM by TR-FRET assay
|
None
|
9.0
%
|
|
Journal : J. Med. Chem.
Title : Selectivity of kinase inhibitor fragments.
Year : 2011
Volume : 54
Issue : 14
First Page : 5131
Last Page : 5143
Authors : Bamborough P, Brown MJ, Christopher JA, Chung CW, Mellor GW.
Abstract : A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
|
Inhibition of FAK expressed in Escherichia coli or baculovirus-infected insect cells at 400 uM by TR-FRET assay
|
None
|
5.0
%
|
|
Journal : J. Med. Chem.
Title : Selectivity of kinase inhibitor fragments.
Year : 2011
Volume : 54
Issue : 14
First Page : 5131
Last Page : 5143
Authors : Bamborough P, Brown MJ, Christopher JA, Chung CW, Mellor GW.
Abstract : A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
|
Inhibition of GSK3-beta expressed in Escherichia coli or baculovirus-infected insect cells using ATP as substrate at 667 uM by fluorescence polarization assay
|
None
|
57.0
%
|
|
Journal : J. Med. Chem.
Title : Selectivity of kinase inhibitor fragments.
Year : 2011
Volume : 54
Issue : 14
First Page : 5131
Last Page : 5143
Authors : Bamborough P, Brown MJ, Christopher JA, Chung CW, Mellor GW.
Abstract : A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
|
Inhibition of IGF1R expressed in Escherichia coli or baculovirus-infected insect cells at 400 uM by TR-FRET assay
|
None
|
44.0
%
|
|
Journal : J. Med. Chem.
Title : Selectivity of kinase inhibitor fragments.
Year : 2011
Volume : 54
Issue : 14
First Page : 5131
Last Page : 5143
Authors : Bamborough P, Brown MJ, Christopher JA, Chung CW, Mellor GW.
Abstract : A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
|
Inhibition of ITK expressed in Escherichia coli or baculovirus-infected insect cells at 667 uM by TR-FRET assay
|
None
|
87.0
%
|
|
Journal : J. Med. Chem.
Title : Selectivity of kinase inhibitor fragments.
Year : 2011
Volume : 54
Issue : 14
First Page : 5131
Last Page : 5143
Authors : Bamborough P, Brown MJ, Christopher JA, Chung CW, Mellor GW.
Abstract : A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
|
Inhibition of JAK3 expressed in Escherichia coli or baculovirus-infected insect cells at 667 uM by TR-FRET assay
|
None
|
78.0
%
|
|
Journal : J. Med. Chem.
Title : Selectivity of kinase inhibitor fragments.
Year : 2011
Volume : 54
Issue : 14
First Page : 5131
Last Page : 5143
Authors : Bamborough P, Brown MJ, Christopher JA, Chung CW, Mellor GW.
Abstract : A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
|
Inhibition of MK2 expressed in Escherichia coli or baculovirus-infected insect cells at 667 uM by IMAP assay
|
None
|
80.0
%
|
|
Journal : J. Med. Chem.
Title : Selectivity of kinase inhibitor fragments.
Year : 2011
Volume : 54
Issue : 14
First Page : 5131
Last Page : 5143
Authors : Bamborough P, Brown MJ, Christopher JA, Chung CW, Mellor GW.
Abstract : A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
|
Inhibition of p38alpha expressed in Escherichia coli or baculovirus-infected insect cells at 667 uM by TR-FRET assay
|
None
|
24.0
%
|
|
Journal : J. Med. Chem.
Title : Selectivity of kinase inhibitor fragments.
Year : 2011
Volume : 54
Issue : 14
First Page : 5131
Last Page : 5143
Authors : Bamborough P, Brown MJ, Christopher JA, Chung CW, Mellor GW.
Abstract : A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
|
Inhibition of PAK2 expressed in Escherichia coli or baculovirus-infected insect cells at 400 uM by IMAP assay
|
None
|
36.0
%
|
|
Journal : J. Med. Chem.
Title : Selectivity of kinase inhibitor fragments.
Year : 2011
Volume : 54
Issue : 14
First Page : 5131
Last Page : 5143
Authors : Bamborough P, Brown MJ, Christopher JA, Chung CW, Mellor GW.
Abstract : A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
|
Inhibition of PDK1 expressed in Escherichia coli or baculovirus-infected insect cells using gamma-[33P]ATP at 400 uM by scintillation proximity assay
|
None
|
77.0
%
|
|
Journal : J. Med. Chem.
Title : Selectivity of kinase inhibitor fragments.
Year : 2011
Volume : 54
Issue : 14
First Page : 5131
Last Page : 5143
Authors : Bamborough P, Brown MJ, Christopher JA, Chung CW, Mellor GW.
Abstract : A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
|
Inhibition of PI3Kalpha expressed in Escherichia coli or baculovirus-infected insect cells using gamma-[33P]ATP at 400 uM by scintillation proximity assay
|
None
|
45.0
%
|
|
Journal : J. Med. Chem.
Title : Selectivity of kinase inhibitor fragments.
Year : 2011
Volume : 54
Issue : 14
First Page : 5131
Last Page : 5143
Authors : Bamborough P, Brown MJ, Christopher JA, Chung CW, Mellor GW.
Abstract : A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
|
Inhibition of PI3Kdelta expressed in Escherichia coli or baculovirus-infected insect cells using gamma-[33P]ATP at 400 uM by scintillation proximity assay
|
None
|
68.0
%
|
|
Journal : J. Med. Chem.
Title : Selectivity of kinase inhibitor fragments.
Year : 2011
Volume : 54
Issue : 14
First Page : 5131
Last Page : 5143
Authors : Bamborough P, Brown MJ, Christopher JA, Chung CW, Mellor GW.
Abstract : A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
|
Inhibition of PIM1 expressed in Escherichia coli or baculovirus-infected insect cells at 400 uM by IMAP assay
|
None
|
20.0
%
|
|
Journal : J. Med. Chem.
Title : Selectivity of kinase inhibitor fragments.
Year : 2011
Volume : 54
Issue : 14
First Page : 5131
Last Page : 5143
Authors : Bamborough P, Brown MJ, Christopher JA, Chung CW, Mellor GW.
Abstract : A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
|
Inhibition of RIP2 expressed in Escherichia coli or baculovirus-infected insect cells at 400 uM by fluorescence polarization assay
|
None
|
11.0
%
|
|
Journal : J. Med. Chem.
Title : Selectivity of kinase inhibitor fragments.
Year : 2011
Volume : 54
Issue : 14
First Page : 5131
Last Page : 5143
Authors : Bamborough P, Brown MJ, Christopher JA, Chung CW, Mellor GW.
Abstract : A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
|
Inhibition of ROCK1 expressed in Escherichia coli or baculovirus-infected insect cells at 400 uM by IMAP assay
|
None
|
80.0
%
|
|
Journal : J. Med. Chem.
Title : Selectivity of kinase inhibitor fragments.
Year : 2011
Volume : 54
Issue : 14
First Page : 5131
Last Page : 5143
Authors : Bamborough P, Brown MJ, Christopher JA, Chung CW, Mellor GW.
Abstract : A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
|
Inhibition of SGK1 expressed in Escherichia coli or baculovirus-infected insect cells at 400 uM by IMAP assay
|
None
|
76.0
%
|
|
Journal : J. Med. Chem.
Title : Selectivity of kinase inhibitor fragments.
Year : 2011
Volume : 54
Issue : 14
First Page : 5131
Last Page : 5143
Authors : Bamborough P, Brown MJ, Christopher JA, Chung CW, Mellor GW.
Abstract : A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
|
Inhibition of SYK expressed in Escherichia coli or baculovirus-infected insect cells at 667 uM by TR-FRET assay
|
None
|
56.0
%
|
|
Journal : J. Med. Chem.
Title : Selectivity of kinase inhibitor fragments.
Year : 2011
Volume : 54
Issue : 14
First Page : 5131
Last Page : 5143
Authors : Bamborough P, Brown MJ, Christopher JA, Chung CW, Mellor GW.
Abstract : A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
90.14
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of sodium fluorescein uptake in OATP1B3-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
81.98
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Displacement of [2,8-3H]-adenosine from Trypanosoma brucei AT1/P2 expressed in bloodstream stage of Trypanosoma brucei brucei B48
|
Trypanosoma brucei
|
280.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships of synthetic cordycepin analogues as experimental therapeutics for African trypanosomiasis.
Year : 2013
Volume : 56
Issue : 24
First Page : 9861
Last Page : 9873
Authors : Vodnala SK, Lundbäck T, Yeheskieli E, Sjöberg B, Gustavsson AL, Svensson R, Olivera GC, Eze AA, de Koning HP, Hammarström LG, Rottenberg ME.
Abstract : Novel methods for treatment of African trypanosomiasis, caused by infection with Trypanosoma brucei are needed. Cordycepin (3'-deoxyadenosine, 1a) is a powerful trypanocidal compound in vitro but is ineffective in vivo because of rapid metabolic degradation by adenosine deaminase (ADA). We elucidated the structural moieties of cordycepin required for trypanocidal activity and designed analogues that retained trypanotoxicity while gaining resistance to ADA-mediated metabolism. 2-Fluorocordycepin (2-fluoro-3'-deoxyadenosine, 1b) was identified as a selective, potent, and ADA-resistant trypanocidal compound that cured T. brucei infection in mice. Compound 1b is transported through the high affinity TbAT1/P2 adenosine transporter and is a substrate of T. b. brucei adenosine kinase. 1b has good preclinical properties suitable for an oral drug, albeit a relatively short plasma half-life. We present a rapid and efficient synthesis of 2-halogenated cordycepins, also useful synthons for the development of additional novel C2-substituted 3'-deoxyadenosine analogues to be evaluated in development of experimental therapeutics.
|
Inhibition of recombinant N-terminal truncated human cytosolic 5'-nucleotidase-2 assessed as inhibition of inosine 5'-monophosphate hydrolysis at 1 mM by rapid green malachite assay
|
Homo sapiens
|
19.0
%
|
|
Journal : J. Med. Chem.
Title : Identification of Noncompetitive Inhibitors of Cytosolic 5'-Nucleotidase II Using a Fragment-Based Approach.
Year : 2015
Volume : 58
Issue : 24
First Page : 9680
Last Page : 9696
Authors : Marton Z, Guillon R, Krimm I, Preeti, Rahimova R, Egron D, Jordheim LP, Aghajari N, Dumontet C, Périgaud C, Lionne C, Peyrottes S, Chaloin L.
Abstract : We used a combined approach based on fragment-based drug design (FBDD) and in silico methods to design potential inhibitors of the cytosolic 5'-nucleotidase II (cN-II), which has been recognized as an important therapeutic target in hematological cancers. Two subgroups of small compounds (including adenine and biaryl moieties) were identified as cN-II binders and a fragment growing strategy guided by molecular docking was considered. Five compounds induced a strong inhibition of the 5'-nucleotidase activity in vitro, and the most potent ones were characterized as noncompetitive inhibitors. Biological evaluation in cancer cell lines showed synergic effect with selected anticancer drugs. Structural studies using X-ray crystallography lead to the identification of new binding sites for two derivatives and of a new crystal form showing important domain swapping. Altogether, the strategy developed herein allowed identifying new original noncompetitive inhibitors against cN-II that act in a synergistic manner with well-known antitumoral agents.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
27.9
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
15.81
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.1
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.1
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
