Ram, TejaSingh, Ankit KumarKumar, AdarshSingh, HarshwardhanPathak, PrateekGrishina, MariaKhalilullah, HabibullahJaremko, MariuszEmwas, Abdul-HamidVerma, AmitaKumar, Pradeep2024-01-212024-08-132024-01-212024-08-132023-08-102632868210.1039/d3md00145hhttp://10.2.3.109/handle/32116/3614MEK1/2 are critical components of the RAS-RAF-MEK-ERK or MAPK signalling pathway that regulates a variety of cellular functions including proliferation, survival, and differentiation. In 1997, a lung cancer cell line was first found to have a MEK mutation (encoding MEK2P298L). MEK is involved in various human cancers such as non-small cell lung cancer (NSCLC), spurious melanoma, and pancreatic, colorectal, basal, breast, and liver cancer. To date, 4 MEK inhibitors i.e., trametinib, cobimetinib, selumetinib, and binimetinib have been approved by the FDA and several are under clinical trials. In this review, we have highlighted structural insights into the MEK1/2 proteins, such as the ?C-helix, catalytic loop, P-loop, F-helix, hydrophobic pocket, and DFG motif. We have also discussed current issues with all FDA-approved MEK inhibitors or drugs under clinical trials and combination therapies to improve the efficacy of clinical drugs. Finally, this study addressed recent developments on synthetic MEK inhibitors (from their discovery in 1997 to 2022), their unique properties, and their relevance to MEK mutant inhibition. � The Royal Society of Chemistry 2023.en-US2 (2 chloro 4 iodoanilino) n cyclopropylmethoxy 3,4 difluorobenzamide2 (2 fluoro 4 iodoanilino) 1,6 dihydro n (2 hydroxyethoxy) 1,5 dimethyl 6 oxonicotinamide3 (2,3 dihydroxypropyl) 6 fluoro 5 (2 fluoro 4 iodoanilino) 8 methylpyrido[2,3 d]pyrimidine 4,7 dione3,4 difluoro 2 (2 fluoro 4 iodoanilino) n (2 hydroxyethoxy) 5 [(3 oxo 1,2 oxazinan 2 yl)methyl]benzamideatezolizumabavutometinibbi 847325binimetinibbya 869766cobimetinibdabrafenibdacarbazinedocetaxeldps 2ebi 1051encorafenibgdc 0623gemcitabineipilimumabkz 001kz 02mirdametinibmitogen activated protein kinase kinase 1mitogen activated protein kinase kinase 2mitogen activated protein kinase kinase inhibitornivolumabpembrolizumabpictilisibpimasertibravoxertinibrdea 119refametinibselumetinibsorafenibtrametinibuprosertiburml 3881vemurafenibvenetoclaxwx 554acneadvanced canceralpha helixbreast cancerchorioretinopathycolon cancerdermatitisdiarrheadifferentiated thyroid cancerfatiguefeverhumanlethargyleukemialiver cell carcinomalung cancermalignant neoplasmmelanomametastatic melanomametastatic uveal melanomanauseaneoplasmneurofibromanon small cell lung cancernonhumanpancreas adenocarcinomapancreas cancerpancreas metastasisperipheral edemaprotein structurerashReviewside effectsignal transductionsolid tumorvomitingReviewhttp://xlink.rsc.org/?DOI=D3MD00145H