2. Academic Validation
  3. Design, synthesis and biological evaluation of novel cyclic malonamide derivatives as selective RIPK1 inhibitors

Design, synthesis and biological evaluation of novel cyclic malonamide derivatives as selective RIPK1 inhibitors

  • Bioorg Med Chem Lett. 2024 Mar 1:100:129643. doi: 10.1016/j.bmcl.2024.129643.
József Levente Petró 1,  Gyula Bényei 2,  Péter Bana 2,  Nikolett Linke 2,  Ferenc Horti 2,  Judit Eszter Szabó 2,  Krisztina Katalin Szalai 2,  Gábor Hornyánszky 3,  István Greiner 2,  János Éles 2
Affiliations

Affiliations

  • 1 Chemical Works of Gedeon Richter Plc, 30-32 Gyömrői Street, Budapest H-1103, Hungary. Electronic address: [email protected].
  • 2 Chemical Works of Gedeon Richter Plc, 30-32 Gyömrői Street, Budapest H-1103, Hungary.
  • 3 Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 8 Budafoki Street, Budapest H-1111, Hungary.
PMID: 38316369 DOI: 10.1016/j.bmcl.2024.129643
Abstract

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) plays a key role in cell death and inflammation. RIPK1 is a well-established therapeutic target, due to the presence of a unique kinase-regulating allosteric pocket, which enables selective inhibition. Herein we used GSK2982772 as our starting point in our discovery campaign. Applying isosteric replacement, we successfully identified the malonamide scaffold, instead of the well-established serine template. Further structural optimization led to the design and synthesis of a series of analog inhibitors. The enantiomers of the most promising compound were tested on 97 different kinases. The active enantiomer proved to be kinase selective.

Keywords

Inhibitor; Malonamide; Necroptosis; RIPK1; Selectivity; Synthesis.

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