|
Binding constant for MEK1 kinase domain
|
None
|
99.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for MEK2 kinase domain
|
None
|
530.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
SANGER: Inhibition of human NCI-H2291 cell growth in a cell viability assay.
|
Homo sapiens
|
761.73
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human NCI-H747 cell growth in a cell viability assay.
|
Homo sapiens
|
350.98
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human NKM-1 cell growth in a cell viability assay.
|
Homo sapiens
|
385.8
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human NOMO-1 cell growth in a cell viability assay.
|
Homo sapiens
|
31.97
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human ONS-76 cell growth in a cell viability assay.
|
Homo sapiens
|
244.53
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human PSN1 cell growth in a cell viability assay.
|
Homo sapiens
|
366.09
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human RCM-1 cell growth in a cell viability assay.
|
Homo sapiens
|
493.85
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human RKO cell growth in a cell viability assay.
|
Homo sapiens
|
248.38
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human RPMI-8226 cell growth in a cell viability assay.
|
Homo sapiens
|
740.0
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human RVH-421 cell growth in a cell viability assay.
|
Homo sapiens
|
279.39
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human SH-4 cell growth in a cell viability assay.
|
Homo sapiens
|
166.48
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human SK-MEL-2 cell growth in a cell viability assay.
|
Homo sapiens
|
405.06
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human SK-MEL-30 cell growth in a cell viability assay.
|
Homo sapiens
|
781.71
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human SK-N-AS cell growth in a cell viability assay.
|
Homo sapiens
|
92.83
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human SW620 cell growth in a cell viability assay.
|
Homo sapiens
|
302.2
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human SW780 cell growth in a cell viability assay.
|
Homo sapiens
|
666.34
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human SW954 cell growth in a cell viability assay.
|
Homo sapiens
|
896.45
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human A101D cell growth in a cell viability assay.
|
Homo sapiens
|
240.33
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human A549 cell growth in a cell viability assay.
|
Homo sapiens
|
214.13
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human ACN cell growth in a cell viability assay.
|
Homo sapiens
|
566.9
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human AsPC-1 cell growth in a cell viability assay.
|
Homo sapiens
|
324.39
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human BHT-101 cell growth in a cell viability assay.
|
Homo sapiens
|
106.93
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human BPH-1 cell growth in a cell viability assay.
|
Homo sapiens
|
182.31
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human BV-173 cell growth in a cell viability assay.
|
Homo sapiens
|
748.02
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human C2BBe1 cell growth in a cell viability assay.
|
Homo sapiens
|
272.59
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human C32 cell growth in a cell viability assay.
|
Homo sapiens
|
98.23
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human CAL-39 cell growth in a cell viability assay.
|
Homo sapiens
|
332.26
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human U-266 cell growth in a cell viability assay.
|
Homo sapiens
|
487.74
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human UACC-257 cell growth in a cell viability assay.
|
Homo sapiens
|
321.84
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human WM-115 cell growth in a cell viability assay.
|
Homo sapiens
|
267.54
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human CHP-212 cell growth in a cell viability assay.
|
Homo sapiens
|
3.153
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human COLO-679 cell growth in a cell viability assay.
|
Homo sapiens
|
341.19
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human COLO-741 cell growth in a cell viability assay.
|
Homo sapiens
|
531.19
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human CP50-MEL-B cell growth in a cell viability assay.
|
Homo sapiens
|
127.94
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human DOK cell growth in a cell viability assay.
|
Homo sapiens
|
147.08
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human DU-4475 cell growth in a cell viability assay.
|
Homo sapiens
|
33.67
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human EM-2 cell growth in a cell viability assay.
|
Homo sapiens
|
511.75
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human EoL-1-cell cell growth in a cell viability assay.
|
Homo sapiens
|
144.76
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human H-EMC-SS cell growth in a cell viability assay.
|
Homo sapiens
|
290.99
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human H9 cell growth in a cell viability assay.
|
Homo sapiens
|
22.88
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human HCC2998 cell growth in a cell viability assay.
|
Homo sapiens
|
269.07
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human HCE-T cell growth in a cell viability assay.
|
Homo sapiens
|
971.31
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human HL-60 cell growth in a cell viability assay.
|
Homo sapiens
|
24.59
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human HO-1-N-1 cell growth in a cell viability assay.
|
Homo sapiens
|
740.52
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human HT-144 cell growth in a cell viability assay.
|
Homo sapiens
|
89.05
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human HT-29 cell growth in a cell viability assay.
|
Homo sapiens
|
873.19
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human HTC-C3 cell growth in a cell viability assay.
|
Homo sapiens
|
214.61
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human HuP-T4 cell growth in a cell viability assay.
|
Homo sapiens
|
195.32
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human JVM-3 cell growth in a cell viability assay.
|
Homo sapiens
|
700.6
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human KG-1 cell growth in a cell viability assay.
|
Homo sapiens
|
895.47
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human KU812 cell growth in a cell viability assay.
|
Homo sapiens
|
211.68
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human KY821 cell growth in a cell viability assay.
|
Homo sapiens
|
107.18
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human LAMA-84 cell growth in a cell viability assay.
|
Homo sapiens
|
456.22
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human LB2241-RCC cell growth in a cell viability assay.
|
Homo sapiens
|
789.91
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human LB2518-MEL cell growth in a cell viability assay.
|
Homo sapiens
|
93.82
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human LOXIMVI cell growth in a cell viability assay.
|
Homo sapiens
|
858.54
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human M14 cell growth in a cell viability assay.
|
Homo sapiens
|
36.89
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human MEL-HO cell growth in a cell viability assay.
|
Homo sapiens
|
138.84
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human MIA-PaCa-2 cell growth in a cell viability assay.
|
Homo sapiens
|
897.68
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human ML-2 cell growth in a cell viability assay.
|
Homo sapiens
|
293.63
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human MV-4-11 cell growth in a cell viability assay.
|
Homo sapiens
|
575.43
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human MZ2-MEL cell growth in a cell viability assay.
|
Homo sapiens
|
394.37
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human Mewo cell growth in a cell viability assay.
|
Homo sapiens
|
521.01
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human NCI-H1437 cell growth in a cell viability assay.
|
Homo sapiens
|
352.85
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
Antiproliferative activity against human MIAPaCa2 cells
|
Homo sapiens
|
142.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Optimization of allosteric MEK inhibitors. Part 1: Venturing into underexplored SAR territories.
Year : 2013
Volume : 23
Issue : 8
First Page : 2384
Last Page : 2390
Authors : Hartung IV, Hitchcock M, Pühler F, Neuhaus R, Scholz A, Hammer S, Petersen K, Siemeister G, Brittain D, Hillig RC.
Abstract : Using PD325901 as a starting point for identifying novel allosteric MEK inhibitors with high cell potency and long-lasting target inhibition in vivo, truncation of its hydroxamic ester headgroup was combined with incorporation of alkyl and aryl ethers at the neighboring ring position. Whereas alkoxy side chains did not yield sufficient levels of cell potency, specifically substituted aryloxy groups allowed for high enzymatic and cellular potencies. Sulfamide 28 was identified as a highly potent MEK inhibitor with nanomolar cell potency against B-RAF (V600E) as well as Ras-mutated cell lines, high metabolic stability and resulting long half-lives. It was efficacious against B-RAF as well as K-Ras driven xenograft models and showed-despite being orally bioavailable and not a P-glycoprotein substrate-much lower brain/plasma exposure ratios than PD325901.
|
Antiproliferative activity against human A375 cells expressing BRAF V600E mutant after 72 hrs by Cell titer-glo assay
|
Homo sapiens
|
31.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Optimization of allosteric MEK inhibitors. Part 1: Venturing into underexplored SAR territories.
Year : 2013
Volume : 23
Issue : 8
First Page : 2384
Last Page : 2390
Authors : Hartung IV, Hitchcock M, Pühler F, Neuhaus R, Scholz A, Hammer S, Petersen K, Siemeister G, Brittain D, Hillig RC.
Abstract : Using PD325901 as a starting point for identifying novel allosteric MEK inhibitors with high cell potency and long-lasting target inhibition in vivo, truncation of its hydroxamic ester headgroup was combined with incorporation of alkyl and aryl ethers at the neighboring ring position. Whereas alkoxy side chains did not yield sufficient levels of cell potency, specifically substituted aryloxy groups allowed for high enzymatic and cellular potencies. Sulfamide 28 was identified as a highly potent MEK inhibitor with nanomolar cell potency against B-RAF (V600E) as well as Ras-mutated cell lines, high metabolic stability and resulting long half-lives. It was efficacious against B-RAF as well as K-Ras driven xenograft models and showed-despite being orally bioavailable and not a P-glycoprotein substrate-much lower brain/plasma exposure ratios than PD325901.
|
Inhibition of MEK1 (unknown origin) after 2 hrs by fluorescence assay
|
Homo sapiens
|
80.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Optimization of allosteric MEK inhibitors. Part 1: Venturing into underexplored SAR territories.
Year : 2013
Volume : 23
Issue : 8
First Page : 2384
Last Page : 2390
Authors : Hartung IV, Hitchcock M, Pühler F, Neuhaus R, Scholz A, Hammer S, Petersen K, Siemeister G, Brittain D, Hillig RC.
Abstract : Using PD325901 as a starting point for identifying novel allosteric MEK inhibitors with high cell potency and long-lasting target inhibition in vivo, truncation of its hydroxamic ester headgroup was combined with incorporation of alkyl and aryl ethers at the neighboring ring position. Whereas alkoxy side chains did not yield sufficient levels of cell potency, specifically substituted aryloxy groups allowed for high enzymatic and cellular potencies. Sulfamide 28 was identified as a highly potent MEK inhibitor with nanomolar cell potency against B-RAF (V600E) as well as Ras-mutated cell lines, high metabolic stability and resulting long half-lives. It was efficacious against B-RAF as well as K-Ras driven xenograft models and showed-despite being orally bioavailable and not a P-glycoprotein substrate-much lower brain/plasma exposure ratios than PD325901.
|
Inhibition of MEK1 (unknown origin) using biotinylated ERK1 as substrate incubated for 2 hrs by fluorescence analysis
|
Homo sapiens
|
31.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Optimization of allosteric MEK inhibitors. Part 2: Taming the sulfamide group balances compound distribution properties.
Year : 2016
Volume : 26
Issue : 1
First Page : 186
Last Page : 193
Authors : Hartung IV, Hammer S, Hitchcock M, Neuhaus R, Scholz A, Siemeister G, Bohlmann R, Hillig RC, Pühler F.
Abstract : Recently, we had identified an unexplored pocket adjacent to the known binding site of allosteric MEK inhibitors which allowed us to design highly potent and in vivo efficacious novel inhibitors. We now report that our initial preclinical candidate, featuring a phenoxy side chain with a sulfamide capping group, displayed human carbonic anhydrase off-target activity and species-dependent blood cell accumulation, which prevented us from advancing this candidate further. Since this sulfamide MEK inhibitor displayed an exceptionally favorable PK profile with low brain penetration potential despite being highly oral bioavailable, we elected to keep the sulfamide capping group intact while taming its unwanted off-target activity by optimizing the structural surroundings. Introduction of a neighboring fluorine atom or installation of a methylene linker reduced hCA potency sufficiently, at the cost of MEK target potency. Switching to a higher fluorinated central core reinstated high MEK potency, leading to two new preclinical candidates with long half-lives, high bioavailabilities, low brain penetration potential and convincing efficacy in a K-Ras-mutated A549 xenograft model.
|
Antiproliferative activity against human HepG2 cells harboring N-Ras mutation
|
Homo sapiens
|
32.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Optimization of allosteric MEK inhibitors. Part 2: Taming the sulfamide group balances compound distribution properties.
Year : 2016
Volume : 26
Issue : 1
First Page : 186
Last Page : 193
Authors : Hartung IV, Hammer S, Hitchcock M, Neuhaus R, Scholz A, Siemeister G, Bohlmann R, Hillig RC, Pühler F.
Abstract : Recently, we had identified an unexplored pocket adjacent to the known binding site of allosteric MEK inhibitors which allowed us to design highly potent and in vivo efficacious novel inhibitors. We now report that our initial preclinical candidate, featuring a phenoxy side chain with a sulfamide capping group, displayed human carbonic anhydrase off-target activity and species-dependent blood cell accumulation, which prevented us from advancing this candidate further. Since this sulfamide MEK inhibitor displayed an exceptionally favorable PK profile with low brain penetration potential despite being highly oral bioavailable, we elected to keep the sulfamide capping group intact while taming its unwanted off-target activity by optimizing the structural surroundings. Introduction of a neighboring fluorine atom or installation of a methylene linker reduced hCA potency sufficiently, at the cost of MEK target potency. Switching to a higher fluorinated central core reinstated high MEK potency, leading to two new preclinical candidates with long half-lives, high bioavailabilities, low brain penetration potential and convincing efficacy in a K-Ras-mutated A549 xenograft model.
|
Antiproliferative activity against human COLO205 cells harboring BRAF mutation
|
Homo sapiens
|
69.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Optimization of allosteric MEK inhibitors. Part 2: Taming the sulfamide group balances compound distribution properties.
Year : 2016
Volume : 26
Issue : 1
First Page : 186
Last Page : 193
Authors : Hartung IV, Hammer S, Hitchcock M, Neuhaus R, Scholz A, Siemeister G, Bohlmann R, Hillig RC, Pühler F.
Abstract : Recently, we had identified an unexplored pocket adjacent to the known binding site of allosteric MEK inhibitors which allowed us to design highly potent and in vivo efficacious novel inhibitors. We now report that our initial preclinical candidate, featuring a phenoxy side chain with a sulfamide capping group, displayed human carbonic anhydrase off-target activity and species-dependent blood cell accumulation, which prevented us from advancing this candidate further. Since this sulfamide MEK inhibitor displayed an exceptionally favorable PK profile with low brain penetration potential despite being highly oral bioavailable, we elected to keep the sulfamide capping group intact while taming its unwanted off-target activity by optimizing the structural surroundings. Introduction of a neighboring fluorine atom or installation of a methylene linker reduced hCA potency sufficiently, at the cost of MEK target potency. Switching to a higher fluorinated central core reinstated high MEK potency, leading to two new preclinical candidates with long half-lives, high bioavailabilities, low brain penetration potential and convincing efficacy in a K-Ras-mutated A549 xenograft model.
|
Inhibition of MEK1 in human HeLa-MaTu matched pair cells assessed as reduction in ERK phosphorylation
|
Homo sapiens
|
14.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Optimization of allosteric MEK inhibitors. Part 2: Taming the sulfamide group balances compound distribution properties.
Year : 2016
Volume : 26
Issue : 1
First Page : 186
Last Page : 193
Authors : Hartung IV, Hammer S, Hitchcock M, Neuhaus R, Scholz A, Siemeister G, Bohlmann R, Hillig RC, Pühler F.
Abstract : Recently, we had identified an unexplored pocket adjacent to the known binding site of allosteric MEK inhibitors which allowed us to design highly potent and in vivo efficacious novel inhibitors. We now report that our initial preclinical candidate, featuring a phenoxy side chain with a sulfamide capping group, displayed human carbonic anhydrase off-target activity and species-dependent blood cell accumulation, which prevented us from advancing this candidate further. Since this sulfamide MEK inhibitor displayed an exceptionally favorable PK profile with low brain penetration potential despite being highly oral bioavailable, we elected to keep the sulfamide capping group intact while taming its unwanted off-target activity by optimizing the structural surroundings. Introduction of a neighboring fluorine atom or installation of a methylene linker reduced hCA potency sufficiently, at the cost of MEK target potency. Switching to a higher fluorinated central core reinstated high MEK potency, leading to two new preclinical candidates with long half-lives, high bioavailabilities, low brain penetration potential and convincing efficacy in a K-Ras-mutated A549 xenograft model.
|
Antiproliferative activity against human SW480 cells after 72 hrs by MTT assay
|
Homo sapiens
|
422.0
nM
|
|
Journal : Eur J Med Chem
Title : Autophagy regulates Selumetinib (AZD6244) induced-apoptosis in colorectal cancer cells.
Year : 2016
Volume : 122
First Page : 611
Last Page : 618
Authors : Grasso S, Pereira GJS, Palmeira-Dos-Santos C, Calgarotto AK, Martínez-Lacaci I, Ferragut JA, Smaili SS, Bincoletto C.
Abstract : As Selumetinib is a MEK1/2 inhibitor that has gained interest as an anti-tumor agent, the present study was designed to investigate autophagy involvement on Selumetinib-induced apoptosis in colorectal cancer (CRC) cells.CRC cells death and cycle studies were assessed by AnnexinV-FITC and PI staining, respectively. Autophagy flux was analysed by Western Blot (LC3II and p62 protein levels) and retroviral infection of SW480 cells for siBecn1 RNA interference experiments. Confocal microscopy was used to determine mCherry-EGFP-LC3 distribution.The Selumetinib effects were concentration-dependent in SW480 cell line. Whereas 1 μM exerted an arrest in the cell cycle (G1 phase), higher concentrations (10 μM) induced cell death, which was accompanied by autophagy blockage in its last stages. Autophagy induction by Rapamycin (RAPA) increased cell survival, whereas pharmacology autophagy inhibition by Bafilomycin A1 (BAF), Chloroquine (CQ) or 3-Methyladenine (3-MA) increased Selumetinib-induced CRC cells death.Altogether, these results suggest that autophagy plays a fundamental role in CRC cells response to Selumetinib. In addition, the combination of Selumetinib with autophagy inhibitors may be a useful therapeutic strategy to enhance its activity against colorectal tumours.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
41.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
52.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
807.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
365.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
209.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Antiproliferative activity against mouse BA/F3 cells harboring KRAS G12D mutant after 72 hrs by CellTiter-Glo assay
|
Mus musculus
|
100.0
nM
|
|
Journal : Bioorg Med Chem
Title : Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors.
Year : 2017
Volume : 25
Issue : 4
First Page : 1320
Last Page : 1328
Authors : Tan L, Gurbani D, Weisberg EL, Jones DS, Rao S, Singer WD, Bernard FM, Mowafy S, Jenney A, Du G, Nonami A, Griffin JD, Lauffenburger DA, Westover KD, Sorger PK, Gray NS.
Abstract : Targeted polypharmacology provides an efficient method of treating diseases such as cancer with complex, multigenic causes provided that compounds with advantageous activity profiles can be discovered. Novel covalent TAK1 inhibitors were validated in cellular contexts for their ability to inhibit the TAK1 kinase and for their polypharmacology. Several inhibitors phenocopied reported TAK1 inhibitor 5Z-7-oxozaenol with comparable efficacy and complementary kinase selectivity profiles. Compound 5 exhibited the greatest potency in RAS-mutated and wild-type RAS cell lines from various cancer types. A biotinylated derivative of 5, 27, was used to verify TAK1 binding in cells. The newly described inhibitors constitute useful tools for further development of multi-targeting TAK1-centered inhibitors for cancer and other diseases.
|
Antiproliferative activity against mouse BA/F3 cells harboring KRAS G12D mutant after 72 hrs in presence of IL-3 by CellTiter-Glo assay
|
Mus musculus
|
1.0
10'-4nM
|
|
Journal : Bioorg Med Chem
Title : Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors.
Year : 2017
Volume : 25
Issue : 4
First Page : 1320
Last Page : 1328
Authors : Tan L, Gurbani D, Weisberg EL, Jones DS, Rao S, Singer WD, Bernard FM, Mowafy S, Jenney A, Du G, Nonami A, Griffin JD, Lauffenburger DA, Westover KD, Sorger PK, Gray NS.
Abstract : Targeted polypharmacology provides an efficient method of treating diseases such as cancer with complex, multigenic causes provided that compounds with advantageous activity profiles can be discovered. Novel covalent TAK1 inhibitors were validated in cellular contexts for their ability to inhibit the TAK1 kinase and for their polypharmacology. Several inhibitors phenocopied reported TAK1 inhibitor 5Z-7-oxozaenol with comparable efficacy and complementary kinase selectivity profiles. Compound 5 exhibited the greatest potency in RAS-mutated and wild-type RAS cell lines from various cancer types. A biotinylated derivative of 5, 27, was used to verify TAK1 binding in cells. The newly described inhibitors constitute useful tools for further development of multi-targeting TAK1-centered inhibitors for cancer and other diseases.
|
Antiproliferative activity against human SW620 cells harboring KRAS G12V mutant after 72 hrs by CellTiter-Glo assay
|
Homo sapiens
|
15.0
nM
|
|
Journal : Bioorg Med Chem
Title : Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors.
Year : 2017
Volume : 25
Issue : 4
First Page : 1320
Last Page : 1328
Authors : Tan L, Gurbani D, Weisberg EL, Jones DS, Rao S, Singer WD, Bernard FM, Mowafy S, Jenney A, Du G, Nonami A, Griffin JD, Lauffenburger DA, Westover KD, Sorger PK, Gray NS.
Abstract : Targeted polypharmacology provides an efficient method of treating diseases such as cancer with complex, multigenic causes provided that compounds with advantageous activity profiles can be discovered. Novel covalent TAK1 inhibitors were validated in cellular contexts for their ability to inhibit the TAK1 kinase and for their polypharmacology. Several inhibitors phenocopied reported TAK1 inhibitor 5Z-7-oxozaenol with comparable efficacy and complementary kinase selectivity profiles. Compound 5 exhibited the greatest potency in RAS-mutated and wild-type RAS cell lines from various cancer types. A biotinylated derivative of 5, 27, was used to verify TAK1 binding in cells. The newly described inhibitors constitute useful tools for further development of multi-targeting TAK1-centered inhibitors for cancer and other diseases.
|
Antiproliferative activity against human SKCO1 cells harboring KRAS G12V mutant after 72 hrs by CellTiter-Glo assay
|
Homo sapiens
|
117.0
nM
|
|
Journal : Bioorg Med Chem
Title : Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors.
Year : 2017
Volume : 25
Issue : 4
First Page : 1320
Last Page : 1328
Authors : Tan L, Gurbani D, Weisberg EL, Jones DS, Rao S, Singer WD, Bernard FM, Mowafy S, Jenney A, Du G, Nonami A, Griffin JD, Lauffenburger DA, Westover KD, Sorger PK, Gray NS.
Abstract : Targeted polypharmacology provides an efficient method of treating diseases such as cancer with complex, multigenic causes provided that compounds with advantageous activity profiles can be discovered. Novel covalent TAK1 inhibitors were validated in cellular contexts for their ability to inhibit the TAK1 kinase and for their polypharmacology. Several inhibitors phenocopied reported TAK1 inhibitor 5Z-7-oxozaenol with comparable efficacy and complementary kinase selectivity profiles. Compound 5 exhibited the greatest potency in RAS-mutated and wild-type RAS cell lines from various cancer types. A biotinylated derivative of 5, 27, was used to verify TAK1 binding in cells. The newly described inhibitors constitute useful tools for further development of multi-targeting TAK1-centered inhibitors for cancer and other diseases.
|
Antiproliferative activity against human PANC1 cells harboring KRAS G12D mutant after 72 hrs by CellTiter-Glo assay
|
Homo sapiens
|
1.0
10'-4nM
|
|
Journal : Bioorg Med Chem
Title : Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors.
Year : 2017
Volume : 25
Issue : 4
First Page : 1320
Last Page : 1328
Authors : Tan L, Gurbani D, Weisberg EL, Jones DS, Rao S, Singer WD, Bernard FM, Mowafy S, Jenney A, Du G, Nonami A, Griffin JD, Lauffenburger DA, Westover KD, Sorger PK, Gray NS.
Abstract : Targeted polypharmacology provides an efficient method of treating diseases such as cancer with complex, multigenic causes provided that compounds with advantageous activity profiles can be discovered. Novel covalent TAK1 inhibitors were validated in cellular contexts for their ability to inhibit the TAK1 kinase and for their polypharmacology. Several inhibitors phenocopied reported TAK1 inhibitor 5Z-7-oxozaenol with comparable efficacy and complementary kinase selectivity profiles. Compound 5 exhibited the greatest potency in RAS-mutated and wild-type RAS cell lines from various cancer types. A biotinylated derivative of 5, 27, was used to verify TAK1 binding in cells. The newly described inhibitors constitute useful tools for further development of multi-targeting TAK1-centered inhibitors for cancer and other diseases.
|
Antiproliferative activity against human AsPC1 cells harboring KRAS G12D mutant after 72 hrs by CellTiter-Glo assay
|
Homo sapiens
|
64.2
nM
|
|
Journal : Bioorg Med Chem
Title : Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors.
Year : 2017
Volume : 25
Issue : 4
First Page : 1320
Last Page : 1328
Authors : Tan L, Gurbani D, Weisberg EL, Jones DS, Rao S, Singer WD, Bernard FM, Mowafy S, Jenney A, Du G, Nonami A, Griffin JD, Lauffenburger DA, Westover KD, Sorger PK, Gray NS.
Abstract : Targeted polypharmacology provides an efficient method of treating diseases such as cancer with complex, multigenic causes provided that compounds with advantageous activity profiles can be discovered. Novel covalent TAK1 inhibitors were validated in cellular contexts for their ability to inhibit the TAK1 kinase and for their polypharmacology. Several inhibitors phenocopied reported TAK1 inhibitor 5Z-7-oxozaenol with comparable efficacy and complementary kinase selectivity profiles. Compound 5 exhibited the greatest potency in RAS-mutated and wild-type RAS cell lines from various cancer types. A biotinylated derivative of 5, 27, was used to verify TAK1 binding in cells. The newly described inhibitors constitute useful tools for further development of multi-targeting TAK1-centered inhibitors for cancer and other diseases.
|
Antiproliferative activity against human SW156 cells harboring wild type KRAS after 72 hrs by CellTiter-Glo assay
|
Homo sapiens
|
1.0
10'-4nM
|
|
Journal : Bioorg Med Chem
Title : Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors.
Year : 2017
Volume : 25
Issue : 4
First Page : 1320
Last Page : 1328
Authors : Tan L, Gurbani D, Weisberg EL, Jones DS, Rao S, Singer WD, Bernard FM, Mowafy S, Jenney A, Du G, Nonami A, Griffin JD, Lauffenburger DA, Westover KD, Sorger PK, Gray NS.
Abstract : Targeted polypharmacology provides an efficient method of treating diseases such as cancer with complex, multigenic causes provided that compounds with advantageous activity profiles can be discovered. Novel covalent TAK1 inhibitors were validated in cellular contexts for their ability to inhibit the TAK1 kinase and for their polypharmacology. Several inhibitors phenocopied reported TAK1 inhibitor 5Z-7-oxozaenol with comparable efficacy and complementary kinase selectivity profiles. Compound 5 exhibited the greatest potency in RAS-mutated and wild-type RAS cell lines from various cancer types. A biotinylated derivative of 5, 27, was used to verify TAK1 binding in cells. The newly described inhibitors constitute useful tools for further development of multi-targeting TAK1-centered inhibitors for cancer and other diseases.
|
Antiproliferative activity against human URMC6 cells harboring wild type KRAS after 72 hrs by CellTiter-Glo assay
|
Homo sapiens
|
1.0
10'-4nM
|
|
Journal : Bioorg Med Chem
Title : Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors.
Year : 2017
Volume : 25
Issue : 4
First Page : 1320
Last Page : 1328
Authors : Tan L, Gurbani D, Weisberg EL, Jones DS, Rao S, Singer WD, Bernard FM, Mowafy S, Jenney A, Du G, Nonami A, Griffin JD, Lauffenburger DA, Westover KD, Sorger PK, Gray NS.
Abstract : Targeted polypharmacology provides an efficient method of treating diseases such as cancer with complex, multigenic causes provided that compounds with advantageous activity profiles can be discovered. Novel covalent TAK1 inhibitors were validated in cellular contexts for their ability to inhibit the TAK1 kinase and for their polypharmacology. Several inhibitors phenocopied reported TAK1 inhibitor 5Z-7-oxozaenol with comparable efficacy and complementary kinase selectivity profiles. Compound 5 exhibited the greatest potency in RAS-mutated and wild-type RAS cell lines from various cancer types. A biotinylated derivative of 5, 27, was used to verify TAK1 binding in cells. The newly described inhibitors constitute useful tools for further development of multi-targeting TAK1-centered inhibitors for cancer and other diseases.
|
Inhibition of MEK1 (unknown origin) using Ser/Thr 03 peptide substrate after 4 hrs by fluorescence assay
|
Homo sapiens
|
9.0
nM
|
|
Journal : Bioorg Med Chem
Title : Discovery of EBI-1051: A novel and orally efficacious MEK inhibitor with benzofuran scaffold.
Year : 2018
Volume : 26
Issue : 3
First Page : 581
Last Page : 589
Authors : Lu B, Huang S, Cao J, Hu Q, Shen R, Wan H, Wang D, Yuan J, Zhang L, Zhang J, Zhang M, Tao W, Zhang L.
Abstract : A novel series of benzodihydrofuran derivatives was developed as potent MEK inhibitors through scaffold hopping based on known clinical compounds. Further SAR exploration and optimization led to another benzofuran series with good oral bioavailability in rats. One of the compounds EBI-1051 (28d) demonstrated excellent in vivo efficacy in colo-205 tumor xenograft models in mouse and is suitable for pre-clinical development studies for the treatment of melanoma and MEK associated cancers. Compared to AZD6244, EBI-1051 showed superior potency in some cancer cell lines such as colon-205, A549 and MDA-MB-231.
|
Antiproliferative activity against human COLO205 cells harboring BRAF mutant/wild type KRAS/wild type PIK3CA after 72 hrs by CCK8 assay
|
Homo sapiens
|
59.0
nM
|
|
Journal : Bioorg Med Chem
Title : Discovery of EBI-1051: A novel and orally efficacious MEK inhibitor with benzofuran scaffold.
Year : 2018
Volume : 26
Issue : 3
First Page : 581
Last Page : 589
Authors : Lu B, Huang S, Cao J, Hu Q, Shen R, Wan H, Wang D, Yuan J, Zhang L, Zhang J, Zhang M, Tao W, Zhang L.
Abstract : A novel series of benzodihydrofuran derivatives was developed as potent MEK inhibitors through scaffold hopping based on known clinical compounds. Further SAR exploration and optimization led to another benzofuran series with good oral bioavailability in rats. One of the compounds EBI-1051 (28d) demonstrated excellent in vivo efficacy in colo-205 tumor xenograft models in mouse and is suitable for pre-clinical development studies for the treatment of melanoma and MEK associated cancers. Compared to AZD6244, EBI-1051 showed superior potency in some cancer cell lines such as colon-205, A549 and MDA-MB-231.
|
Inhibition of RAF/MEK/ERK in human A549 cells assessed as reduction in ERK phosphorylation at 1 uM after 8 hrs by Western blot analysis relative to control
|
Homo sapiens
|
65.0
%
|
|
Journal : Bioorg Med Chem
Title : Dual inhibitors of RAF-MEK-ERK and PI3K-PDK1-AKT pathways: Design, synthesis and preliminary anticancer activity studies of 3-substituted-5-(phenylamino) indolone derivatives.
Year : 2019
Volume : 27
Issue : 6
First Page : 944
Last Page : 954
Authors : Yu Z, Chen Z, Su Q, Ye S, Yuan H, Kuai M, Lv M, Tu Z, Yang X, Liu R, Hu G, Li Q.
Abstract : The dysfunction and mutual compensatory activation of RAF-MEK-ERK and PI3K-PDK1-AKT pathways have been demonstrated as the hallmarks in several primary and recurrent cancers. The strategy of concurrent blocking of these two pathways shows clinical merits on effective cancer therapy, such as combinatory treatments and dual-pathway inhibitors. Herein, we report a novel prototype of dual-pathway inhibitors by means of merging the core structural scaffolds of a MEK1 inhibitor and a PDK1 inhibitor. A library of 43 compounds that categorized into three series (Series I-III) was synthesized and tested for antitumor activity in lung cancer cells. The results from structure-activity relationship (SAR) analysis showed the following order of antitumor activity that 3-hydroxy-5-(phenylamino) indolone (Series III) > 3-alkenyl-5-(phenylamino) indolone (Series I) > 3-alkyl-5-(phenylamino) indolone (Series II). A lead compound 9za in Series III showed most potent antitumor activity with IC<sub>50</sub> value of 1.8 ± 0.8 µM in A549 cells. Moreover, antitumor mechanism study demonstrated that 9za exerted significant apoptotic effect, and cellular signal pathway analysis revealed the potent blockage of phosphorylation levels of ERK and AKT in RAF-MEK-ERK and PI3K-PDK1-AKT pathways, respectively. The results reported here provide robust experimental basis for the discovery and optimization of dual pathway agents for anti-lung cancer therapy.
|
Inhibition of MEK (unknown origin)
|
Homo sapiens
|
14.0
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis, biological evaluation, QSAR analysis and molecular modelling of new thiazol-benzimidazoles as EGFR inhibitors.
Year : 2020
Volume : 28
Issue : 18
First Page : 115657
Last Page : 115657
Authors : Srour AM,Ahmed NS,Abd El-Karim SS,Anwar MM,El-Hallouty SM
Abstract : Heterocyclic rings such as thiazole and benzimidazole are considered as privileged structures, since they constitute several FDA-approved drugs for cancer treatment. In this work, a new set of 2-(2-(substituted) hydrazinyl)-4-(1-methyl-1H-benzo[d]imidazol-2-yl) thiazoles 4a-q were designed as epidermal growth factor receptor (EGFR) inhibitors and synthesized using concise synthetic methods. The new target compounds have been evaluated in vitro for their suppression activity against EGFR TK. Compounds 4n, 4h, 4i, 4a and 4d exhibited significant potency in comparison with erlotinib which served as a reference drug (IC50, 71.67-152.59 nM; IC50 erlotinib, 152.59 nM). Furthermore, MTT assay revealed that compounds 4j, 4a, 4f, 4h, 4n produced the most promising cytotoxic potency against the human breast cancer cell line (MCF-7) (IC50; 5.96-11.91 µM; IC50 erlotinib; 4.15 µM). Compound 4a showed promising activity as EGFR TK inhibitor as well as anti-breast cancer agent. In addition, 4a induced apoptotic effect and cell cycle arrest at G2/M phase preventing the mitotic cycle in MCF-7 cells. Moreover, 4a upregulated the oncogenic parameters; caspase-3, p53, Bax/Bcl-2 as well as it inhibited the level of PARP-1 enzyme. QSAR study was carried out for the new derivatives and it revealed the goodness of the models. Furthermore, molecular docking studies represented the binding modes of the promising compounds in the active pocket of EGFR.
