7PQV
MEK1 IN COMPLEX WITH COMPOUND 7
Summary for 7PQV
| Entry DOI | 10.2210/pdb7pqv/pdb |
| Descriptor | Dual specificity mitogen-activated protein kinase kinase 1, 8-(2-chloranyl-4-methoxy-phenyl)-7-fluoranyl-1-piperidin-4-yl-imidazo[4,5-c]quinoline, CALCIUM ION, ... (5 entities in total) |
| Functional Keywords | mek1 mitogen-activated protein kinase 1, kinase inhibitor, anti-cancer drug, signaling protein |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 39022.75 |
| Authors | Moebitz, H. (deposition date: 2021-09-20, release date: 2022-03-16, Last modification date: 2024-06-19) |
| Primary citation | Poddutoori, R.,Aardalen, K.,Aithal, K.,Barahagar, S.S.,Belliappa, C.,Bock, M.,Chelur, S.,Gerken, A.,Gopinath, S.,Gruenenfelder, B.,Kiffe, M.,Krishnaswami, M.,Langowski, J.,Madapa, S.,Narayanan, K.,Pandit, C.,Panigrahi, S.K.,Perrone, M.,Potakamuri, R.K.,Ramachandra, M.,Ramanathan, A.,Ramos, R.,Sager, E.,Samajdar, S.,Subramanya, H.S.,Thimmasandra, D.S.,Venetsanakos, E.,Mobitz, H. Discovery of MAP855, an Efficacious and Selective MEK1/2 Inhibitor with an ATP-Competitive Mode of Action. J.Med.Chem., 65:4350-4366, 2022 Cited by PubMed Abstract: Mutations in MEK1/2 have been described as a resistance mechanism to BRAF/MEK inhibitor treatment. We report the discovery of a novel ATP-competitive MEK1/2 inhibitor with efficacy in wildtype (WT) and mutant MEK12 models. Starting from a HTS hit, we obtained selective, cellularly active compounds that showed equipotent inhibition of WT MEK1/2 and a panel of MEK1/2 mutant cell lines. Using a structure-based approach, the optimization addressed the liabilities by systematic analysis of molecular matched pairs (MMPs) and ligand conformation. Addition of only three heavy atoms to early tool compound removed Cyp3A4 liabilities and increased the cellular potency by 100-fold, while reducing log by 5 units. Profiling of MAP855, compound , in pharmacokinetic-pharmacodynamic and efficacy studies in BRAF-mutant models showed comparable efficacy to clinical MEK1/2 inhibitors. Compound is a novel highly potent and selective MEK1/2 kinase inhibitor with equipotent inhibition of WT and mutant MEK1/2, whose drug-like properties allow further investigation in the mutant MEK setting upon BRAF/MEK therapy. PubMed: 35195996DOI: 10.1021/acs.jmedchem.1c02192 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.13 Å) |
Structure validation
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