7XLP

MEK1 bound to DS03090629

Summary for 7XLP

• Entry DOI: 10.2210/pdb7xlp/pdb
• Descriptor: Dual specificity mitogen-activated protein kinase kinase 1, (1~{R},3~{S})-3-[[6-[2-chloranyl-4-(4-methylpyrimidin-2-yl)oxy-phenyl]-3-methyl-1~{H}-indazol-4-yl]oxy]cyclohexan-1-amine, DIMETHYL SULFOXIDE, ... (5 entities in total)
• Functional Keywords: kinase, inhibitor, complex, atp competitive, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 39579.21

Authors

Kishikawa, S.,Takano, K.,Ubukata, O.,Hanzawa, H. (deposition date: 2022-04-22, release date: 2023-03-01, Last modification date: 2023-11-29)

Primary citation

Takano, K.,Munehira, Y.,Hatanaka, M.,Murakami, R.,Shibata, Y.,Shida, T.,Takeuchi, K.,Takechi, S.,Tabata, T.,Shimada, T.,Kishikawa, S.,Matsui, Y.,Ubukata, O.,Seki, T.,Kaneta, Y.
Discovery of a Novel ATP-Competitive MEK Inhibitor DS03090629 that Overcomes Resistance Conferred by BRAF Overexpression in BRAF-Mutated Melanoma.
Mol.Cancer Ther., 22:317-332, 2023

PubMed Abstract: Patients with melanoma with activating BRAF mutations (BRAF V600E/K) initially respond to combination therapy of BRAF and MEK inhibitors. However, their clinical efficacy is limited by acquired resistance, in some cases driven by amplification of the mutant BRAF gene and subsequent reactivation of the MAPK pathway. DS03090629 is a novel and orally available MEK inhibitor that inhibits MEK in an ATP-competitive manner. In both in vitro and in vivo settings, potent inhibition of MEK by DS03090629 or its combination with the BRAF inhibitor dabrafenib was demonstrated in a mutant BRAF-overexpressing melanoma cell line model that exhibited a higher MEK phosphorylation level than the parental cell line and then became resistant to dabrafenib and the MEK inhibitor trametinib. DS03090629 also exhibited superior efficacy against a melanoma cell line-expressing mutant MEK1 protein compared with dabrafenib and trametinib. Biophysical analysis revealed that DS03090629 retained its affinity for the MEK protein regardless of its phosphorylation status, whereas the affinity of trametinib declined when the MEK protein was phosphorylated. These results suggest that DS03090629 may be a novel therapeutic option for patients who acquire resistance to the current BRAF- and MEK-targeting therapies.

PubMed: 36622773
DOI: 10.1158/1535-7163.MCT-22-0306

Experimental method

X-RAY DIFFRACTION (2.1 Å)