Discovery of a Potent, Selective, and Orally Available MTHFD2 Inhibitor (DS18561882) with in Vivo Antitumor Activity.
J Med Chem
; 62(22): 10204-10220, 2019 11 27.
Article
en En
| MEDLINE
| ID: mdl-31638799
ABSTRACT
We report the discovery of a potent and isozyme-selective MTHFD2 inhibitor, DS18561882 (2). Through investigation of the substituents on our tricyclic coumarin scaffold (1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one), MTHFD2 inhibitory activity was shown to be elevated by incorporating an amine moiety at the 8-position and a methyl group at the 7-position of the initial lead 1. X-ray structure analysis revealed that a key interaction for enhanced potency was salt bridge formation between the amine moiety and the diphosphate linker of an NAD+ cofactor. Furthermore, ortho-substituted sulfonamide in place of benzoic acid of 1 significantly improved cell permeability and cell-based growth inhibition against a human breast cancer cell line. The thus-optimized DS18561882 showed the strongest cell-based activity (GI50 = 140 nM) in the class, a good oral pharmacokinetic profile, and thereby tumor growth inhibition in a mouse xenograft model upon oral administration.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Enzimas Multifuncionales
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Aminohidrolasas
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Metilenotetrahidrofolato Deshidrogenasa (NADP)
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Antineoplásicos
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2019
Tipo del documento:
Article
País de afiliación:
Japón