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| Autores principales: | , , , , , , , , , , |
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| Formato: | Artículo Open Access |
| Publicado: |
Wiley
2026
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| Materias: | |
| Acceso en línea: | https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.70324 |
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- Design and Synthesis of Pyrimidino[4,5‐ d ]Pyrimidine‐Based Compounds as Potent B‐RAF V600E Inhibitors Eleftheria A. Georgiou Kalliopi Christopoulou Amalia D. Kalampaliki Aikaterini F. Giannopoulou Eleftheria Chatziorfanou Vivi Bafiti Andreas Krämer Athanasios Papakyriakou Dimitrios J. Stravopodis Stefan Knapp Ioannis K. Kostakis ChemMedChem The mitogen‐activated protein kinase (MAPK) pathway plays a central role in regulating cellular proliferation, differentiation, and survival, and its aberrant activation is a hallmark of numerous cancers. B‐RAF, a key kinase in this pathway, is frequently mutated, with the B‐RAF V600E variant being highly prevalent in melanoma. Here, we report the design, synthesis, and biological evaluation of novel pyrimido[4,5‐ d ]pyrimidine‐based compounds targeting B‐RAF. The compounds were rationally designed to incorporate key pharmacophoric features of known B‐RAF inhibitors to enhance selectivity and potency against B‐RAF. Kinase profiling using differential scanning fluorimetry (DSF) and isothermal titration calorimetry (ITC) showed that compound 15 binds selectively to B‐RAF V600E ( K d = 98 nM) with minimal off‐target interactions. Docking studies supported a type‐II binding mode in a DFG‐out/αC‐helix‐in conformation, highlighting key hydrogen‐bonding and hydrophobic interactions within the ATP‐binding cleft. Despite its strong biochemical profile, 15 showed only modest antiproliferative activity in T24 and WM266−4 cancer cells, suggesting limitations related to cellular permeability or efflux. In contrast, compounds 16 , 17 , and 22 displayed marked cellular activity despite limited B‐RAF inhibition, indicating potential contributions from alternative kinases or yet unidentified off‐target mechanisms. The large DSF Tm shifts observed established the poorly exploited pyrimido[4,5‐ d ]pyrimidines as interesting ATP mimetic scaffolds for kinase inhibitor development. 10.1002/cmdc.70324 http://creativecommons.org/licenses/by/4.0/