Discovery of MAP855, an Efficacious and Selective MEK1/2 Inhibitor with an ATP-Competitive Mode of Action was written by Poddutoori, Ramulu;Aardalen, Kimberly;Aithal, Kiran;Barahagar, Sanjeev Surendranath;Belliappa, Charamanna;Bock, Mark;Chelur, Shekar;Gerken, Andrea;Gopinath, Sreevalsam;Gruenenfelder, Bjoern;Kiffe, Michael;Krishnaswami, Maithreyi;Langowski, John;Madapa, Sudharshan;Narayanan, Kishore;Pandit, Chetan;Panigrahi, Sunil Kumar;Perrone, Mark;Potakamuri, Ravi Kumar;Ramachandra, Murali;Ramanathan, Anuradha;Ramos, Rita;Sager, Emine;Samajdar, Susanta;Subramanya, Hosahalli S.;Thimmasandra, Devaraja Seethappa;Venetsanakos, Eleni;Mobitz, Henrik. And the article was included in Journal of Medicinal Chemistry in 2022.Formula: C9H19N3O2 This article mentions the following:
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 anal. of mol. matched pairs (MMPs) and ligand conformation. Addition of only three heavy atoms to early tool compound 6 removed Cyp3A4 liabilities and increased the cellular potency by 100-fold, while reducing log P by 5 units. Profiling of MAP855, compound 30, in pharmacokinetic-pharmacodynamic and efficacy studies in BRAF-mutant models showed comparable efficacy to clin. MEK1/2 inhibitors. Compound 30 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. In the experiment, the researchers used many compounds, for example, tert-Butyl 4-aminopiperazine-1-carboxylate (cas: 118753-66-5Formula: C9H19N3O2).
tert-Butyl 4-aminopiperazine-1-carboxylate (cas: 118753-66-5) belongs to piperidine derivatives. The piperidine ring can be found not only in more than half of the currently known structures of alkaloids, but also in many natural or synthetic compounds with interesting biological activities. Several piperidine alkaloids isolated from natural herbs, were found to exhibit antiproliferation and antimetastatic effects on various types of cancers both in vitro and in vivo for example Piperine, Evodiamine, Matrine, Berberine and Tetrandine.Formula: C9H19N3O2
Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem