Discovery of MAP855, an Efficacious and Selective MEK1/2 Inhibitor with an ATP-Competitive Mode of Action

Poddutoori Ramulu; Aardalen Kimberly; Aithal KiranBarahagar Sanjeev SurendranathBelliappa CharamannaBock MarkChelur ShekarGerken AndreaGopinath SreevalsamGruenenfelder BjoernKiffe MichaelKrishnaswami MaithreyiLangowski JohnMadapa SudharshanNarayanan KishorePandit ChetanPanigrahi Sunil KumarPerrone MarkPotakamuri Ravi KumarRamachandra MuraliRamanathan AnuradhaRamos RitaSager EmineSamajdar SusantaSubramanya Hosahalli S.Thimmasandra Devaraja SeethappaVenetsanakos EleniMobitz Henrik

首页> 外文期刊>Journal of Medicinal Chemistry >Discovery of MAP855, an Efficacious and Selective MEK1/2 Inhibitor with an ATP-Competitive Mode of Action

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Discovery of MAP855, an Efficacious and Selective MEK1/2 Inhibitor with an ATP-Competitive Mode of Action

机译：Discovery of MAP855, an Efficacious and Selective MEK1/2 Inhibitor with an ATP-Competitive Mode of Action

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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 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 clinical 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.

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《Journal of Medicinal Chemistry》 |2022年第5期|4350-4366|共17页
作者
Poddutoori Ramulu; Aardalen Kimberly; Aithal KiranBarahagar Sanjeev SurendranathBelliappa CharamannaBock MarkChelur ShekarGerken AndreaGopinath SreevalsamGruenenfelder BjoernKiffe MichaelKrishnaswami MaithreyiLangowski JohnMadapa SudharshanNarayanan KishorePandit ChetanPanigrahi Sunil KumarPerrone MarkPotakamuri Ravi KumarRamachandra MuraliRamanathan AnuradhaRamos RitaSager EmineSamajdar SusantaSubramanya Hosahalli S.Thimmasandra Devaraja SeethappaVenetsanakos EleniMobitz Henrik;
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作者单位

Novartis Inst BioMed Res;

Aurigene Discovery Technol Ltd;

Biocon Bristol Myers Squibb R&D Ctr667 Cache Creek Dr,POB 3384, Jackson, WY 83001 USASyngene Int LtdNovartis Pharma AG;

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正文语种英语
中图分类药学;
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MUTATIONS; BRAF; RAF; RESISTANCE; EGFR;

Discovery of MAP855, an Efficacious and Selective MEK1/2 Inhibitor with an ATP-Competitive Mode of Action

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