MEK1 inhibitors(Dual specificity mitogen-activated protein kinase kinase 1 inhibitors), MEK2 inhibitors(Dual specificity mitogen-activated protein kinase kinase 2 inhibitors)

Therapeutic Areas

Neoplasms

Active Indication

Neoplasms

Inactive Indication-

Originator Organization

Aurigene Oncology Ltd.

Novartis Institutes for Biomedical Research, Inc.

Active Organization

Aurigene Oncology Ltd.

Novartis Institutes for Biomedical Research, Inc.

Inactive Organization-

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC28H23ClF2N6O3

InChIKeyWZZBNLYBHUDSHF-DHLKQENFSA-N

CAS Registry1660107-77-6

100 Clinical Results associated with MAP-855

100 Translational Medicine associated with MAP-855

100 Patents (Medical) associated with MAP-855

Literatures (Medical) associated with MAP-855

10 Mar 2022·Journal of Medicinal ChemistryQ1 · MEDICINE

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

Q1 · MEDICINE

Article

Author: Bock, Mark ; Langowski, John ; Perrone, Mark ; Ramanathan, Anuradha ; Chelur, Shekar ; Pandit, Chetan ; Möbitz, Henrik ; Aithal, Kiran ; Panigrahi, Sunil Kumar ; Gerken, Andrea ; Ramachandra, Murali ; Sager, Emine ; Barahagar, Sanjeev Surendranath ; Subramanya, Hosahalli S. ; Gopinath, Sreevalsam ; Gruenenfelder, Bjoern ; Venetsanakos, Eleni ; Kiffe, Michael ; Thimmasandra, Devaraja Seethappa ; Narayanan, Kishore ; Aardalen, Kimberly ; Samajdar, Susanta ; Potakamuri, Ravi Kumar ; Krishnaswami, Maithreyi ; Belliappa, Charamanna ; Ramos, Rita ; Poddutoori, Ramulu ; Madapa, Sudharshan

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.

CancersQ2 · MEDICINE

Allosteric and ATP-Competitive MEK-Inhibition in a Novel Spitzoid Melanoma Model with a RAF- and Phosphorylation-Independent Mutation

Q2 · MEDICINE

ArticleOA

Author: Schadendorf, Dirk ; Hegedüs, Balázs ; Tóvári, József ; Bánkfalvi, Ágnes ; Kovács, Ildikó ; Okumus, Özlem ; Aigner, Clemens ; Hegedüs, Luca ; Livingstone, Elisabeth ; Baranyi, Marcell ; Döme, Balázs

Spitzoid melanoma is a rare malignancy with histological characteristics similar to Spitz nevus. It has a diverse genetic background and in adults, a similarly grim clinical outcome as conventional malignant melanoma. We established a spitzoid melanoma cell line (PF130) from the pleural effusion sample of a 37-year-old male patient. We found that the cell line carries a rare MEK1 mutation (pGlu102_Lys104delinsGln) that belongs to the RAF- and phosphorylation-independent subgroup of MEK1 alternations supposedly insensitive to allosteric MEK inhibitors. The in vivo tumorigenicity was tested in three different models by injecting the cells subcutaneously, intravenously or into the thoracic cavity of SCID mice. In the intrapleural model, macroscopic tumors formed in the chest cavity after two months, while subcutaneously and intravenously delivered cells showed limited growth. In vitro, trametinib—but not selumentinib—and the ATP-competitive MEK inhibitor MAP855 strongly decreased the viability of the cells and induced cell death. In vivo, trametinib but not MAP855 significantly reduced tumor growth in the intrapleural model. To the best of our knowledge, this is the first patient-derived melanoma model with RAF- and phosphorylation-independent MEK mutation and we demonstrated its sensitivity to trametinib.

100 Deals associated with MAP-855

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	India	Aurigene Oncology Ltd.	23 Feb 2022
Neoplasms	Preclinical	United States	Novartis Institutes for Biomedical Research, Inc.	23 Feb 2022

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