1656989-76-2Relevant articles and documents
Discovery of MAP855, an Efficacious and Selective MEK1/2 Inhibitor with an ATP-Competitive Mode of Action
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,M?bitz, Henrik,Madapa, Sudharshan,Narayanan, Kishore,Pandit, Chetan,Panigrahi, Sunil Kumar,Perrone, Mark,Poddutoori, Ramulu,Potakamuri, Ravi Kumar,Ramachandra, Murali,Ramanathan, Anuradha,Ramos, Rita,Sager, Emine,Samajdar, Susanta,Subramanya, Hosahalli S.,Thimmasandra, Devaraja Seethappa,Venetsanakos, Eleni
, p. 4350 - 4366 (2022/03/14)
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.
DUAL ATM AND DNA-PK INHIBITORS FOR USE IN ANTI-TUMOR THERAPY
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Page/Page column 149, (2019/11/12)
Provided herein are compounds of the Formula (I), (II), and (III), as well as pharmaceutically acceptable salts thereof, wherein the substituents are those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of oncologic diseases.
COMPOUNDS AND COMPOSITIONS AS INHIBITORS OF MEK
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, (2015/02/25)
The present invention relates to compounds of formula I: in which n, R1, R2, R3 and R4 are defined in the Summary of the Invention; capable of inhibiting the activity of MEK. The invention further provides a pro
COMPOUNDS AND COMPOSITIONS AS INHIBITORS OF MEK
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, (2015/02/25)
The present invention relates to compounds of formula I in which n, R1, R2, R3a, R4 and R5 are defined in the Summary of the Invention; capable of inhibiting the activity of MEK. The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management of hyperproliferative diseases like cancer.
COMPOUNDS AND COMPOSITIONS AS INHIBITORS OF MEK
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Paragraph 00214, (2015/02/25)
The present invention relates to compounds of formula I: in which n, Y, R1, R2, R3a, R4 and R5 are defined in the Summary of the Invention; capable of inhibiting the activity of MEK. The invention fur
COMPOUNDS AND COMPOSITIONS AS INHIBITORS OF MEK
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Paragraph 0340; 0341, (2015/02/25)
The present invention relates to compounds of formula I: in which n, R1, R2, R3a, R4 and R5 are defined in the Summary of the Invention; capable of inhibiting the activity of MEK. The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management of hyperproliferative diseases like cancer.
