2. Academic Validation
  3. Harnessing dual-mode RIPK1 ligands for cross-species anti-necroptosis inhibitor compounds

Harnessing dual-mode RIPK1 ligands for cross-species anti-necroptosis inhibitor compounds

  • Bioorg Med Chem Lett. 2024 Nov 15:113:129970. doi: 10.1016/j.bmcl.2024.129970.
József Levente Petró 1,  Péter Bana 2,  Nikolett Linke 2,  Judit Eszter Szabó 2,  Krisztina Katalin Szalai 2,  Ildikó Kálomista 2,  Csaba Gábor Vass 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; Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Műegyetem rkp. 3., H-1111 Budapest, Hungary. Electronic address: petrojl@gedeonrichter.com.
  • 2 Chemical Works of Gedeon Richter Plc, 30-32 Gyömrői Street, Budapest H-1103, Hungary.
  • 3 Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Műegyetem rkp. 3., H-1111 Budapest, Hungary.
PMID: 39306047 DOI: 10.1016/j.bmcl.2024.129970
Abstract

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) has a crucial role in cell death and inflammation. A promising approach to develop novel inhibitors of RIPK1 mediated Necroptosis is to mix the different binding modes of the known RIPK1 inhibitors into one molecule. Herein we report the synthesis and biological evaluation of novel mixed type inhibitors. Using Eclitasertib as a starting point, and applying our previous, published knowledge regarding cyclic malonamides, we successfully identified a library of active compounds. The active enantiomer of the most balanced and promising compound was subjected to pharmacokinetics and in vivo hypothermia study in mice.

Keywords

Inhibitor; Mixed type; Necroptosis; Pharmacokinetics; RIPK1; Synthesis.

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