Target Binding Site Detail
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| Target ID | T35940 | Target Info | |||
| Target Name | ERK activator kinase 1 (MEK1) | ||||
| Synonyms | PRKMK1; Mitogen-activated protein kinase kinase 1; MKK1; MEK 1; MAPKK 1; MAPK/ERKkinase 1; MAPK/ERK kinase 1; MAP kinase kinase 1; Dual specificity mitogen-activated protein kinase kinase 1 | ||||
| Target Type | Clinical trial Target | ||||
| Gene Name | MAP2K1 | ||||
| Biochemical Class | Kinase | ||||
| UniProt ID | |||||
| Ligand General Information | Top | ||||
|---|---|---|---|---|---|
| Ligand Name | Cotellic | Ligand Info | |||
| Canonical SMILES | C1CCNC(C1)C2(CN(C2)C(=O)C3=C(C(=C(C=C3)F)F)NC4=C(C=C(C=C4)I)F)O | ||||
| InChI | 1S/C21H21F3IN3O2/c22-14-6-5-13(19(18(14)24)27-16-7-4-12(25)9-15(16)23)20(29)28-10-21(30,11-28)17-3-1-2-8-26-17/h4-7,9,17,26-27,30H,1-3,8,10-11H2/t17-/m0/s1 | ||||
| InChIKey | BSMCAPRUBJMWDF-KRWDZBQOSA-N | ||||
| PubChem Compound ID | 16222096 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| PDB ID: 7M0V Crystal structure of the BRAF:MEK1 kinases in complex with AMPPNP and Cobimetinib | ||||||
| Method | X-ray diffraction | Resolution | 3.16 Å | Mutation | Yes | [1] |
| PDB Sequence |
LDEQQRKRLE
51 AFLTQKQKVG61 ELKDDDFEKI71 SELGAGNGGV81 VFKVSHKPSG91 LVMARKLIHL 101 EIKPAIRNQI111 IRELQVLHEC121 NSPYIVGFYG131 AFYSDGEISI141 CMEHMDGGSL 151 DQVLKKAGRI161 PEQILGKVSI171 AVIKGLTYLR181 EKHKIMHRDV191 KPSNILVNSR 201 GEIKLCDFGV211 SGQLIDAMAN221 AFVGTRSYMS231 PERLQGTHYS241 VQSDIWSMGL 251 SLVEMAVGRY261 PIPPPDAKEL271 ELMPMAIFEL313 LDYIVNEPPP323 KLPSGVFSLE 333 FQDFVNKCLI343 KNPAERADLK353 QLMVHAFIKR363 SDAEEVDFAG373 WLCSTIGLNQ 383
|
|||||
|
|
LYS97
3.001
ILE99
4.679
LEU115
3.322
LEU118
3.929
ILE126
4.896
VAL127
3.658
GLY128
4.417
PHE129
4.739
ILE141
3.813
MET143
3.743
ASP190
3.653
LYS192
4.280
|
|||||
| PDB ID: 4LMN Crystal Structure of MEK1 kinase bound to GDC0973 | ||||||
| Method | X-ray diffraction | Resolution | 2.80 Å | Mutation | No | [2] |
| PDB Sequence |
MELKDDDFEK
70 ISELGAGNGG80 VVFKVSHKPS90 GLVMARKLIH100 LEIKPAIRNQ110 IIRELQVLHE 120 CNSPYIVGFY130 GAFYSDGEIS140 ICMEHMDGGS150 LDQVLKKAGR160 IPEQILGKVS 170 IAVIKGLTYL180 REKHKIMHRD190 VKPSNILVNS200 RGEIKLCDFG210 VSGQLIDSMA 220 NSFVGTRSYM230 SPERLQGTHY240 SVQSDIWSMG250 LSLVEMAVGR260 YPIPPPDAKE 270 LELMFPPMAI310 FELLDYIVNE320 PPPKLPSGVF330 SLEFQDFVNK340 CLIKNPAERA 350 DLKQLMVHAF360 IKRSDAEEVD370 FAGWLCSTIG380 LN
|
|||||
|
|
LYS97
3.199
ILE99
4.356
LEU115
3.377
LEU118
3.863
ILE126
4.960
VAL127
3.321
GLY128
4.436
PHE129
4.803
ILE141
3.427
MET143
3.604
ASP190
2.828
LYS192
4.792
|
|||||
| PDB ID: 4AN2 Crystal structures of human MEK1 with carboxamide-based allosteric inhibitor XL518 (GDC-0973), or related analogs. | ||||||
| Method | X-ray diffraction | Resolution | 2.50 Å | Mutation | Yes | [3] |
| PDB Sequence |
MALGELKDDD
67 FEKISELGAG77 NGGVVFKVSH87 KPSGLVMARK97 LIHLEIKPAI107 RNQIIRELQV 117 LHECNSPYIV127 GFYGAFYSDG137 EISICMEHMD147 GGSLDQVLKK157 AGRIPEQILG 167 KVSIAVIKGL177 TYLREKHKIM187 HRDVKPSNIL197 VNSRGEIKLC207 DFGVSGQLID 217 EMANEFVGTR227 SYMSPERLQG237 THYSVQSDIW247 SMGLSLVEMA257 VGRYPRPPMA 309 IFELLDYIVN319 EPPPKLPSAV329 FSLEFQDFVN339 KCLIKNPAER349 ADLKQLMVHA 359 FIKRSDAEEV369 DFAGWLCSTI379 GL
|
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|
|
ASN78
3.576
LYS97
2.630
ILE99
4.650
LEU115
3.557
LEU118
3.863
VAL127
3.578
GLY128
4.706
ILE141
3.460
MET143
3.633
ASP190
2.724
LYS192
3.866
ASN195
3.230
CYS207
4.638
|
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | Allosteric MEK inhibitors act on BRAF/MEK complexes to block MEK activation. Proc Natl Acad Sci U S A. 2021 Sep 7;118(36):e2107207118. | ||||
| REF 2 | Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers. Nature. 2013 Sep 12;501(7466):232-6. | ||||
| REF 3 | Novel Carboxamide-Based Allosteric MEK Inhibitors: Discovery and Optimization Efforts toward XL518 (GDC-0973). ACS Med Chem Lett. 2012 Apr 9;3(5):416-21. | ||||
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