Új megközelítés egy feltörekvő neurodegenerációs célpont kutatásában = Novel approach to research on an emerging neurodegeneration target

Petró, József Levente and Hornyánszky, Gábor and Éles, János (2026) Új megközelítés egy feltörekvő neurodegenerációs célpont kutatásában = Novel approach to research on an emerging neurodegeneration target. SCIENTIA ET SECURITAS, 6 (4). pp. 441-447. ISSN 3057-9759

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Abstract

A RIP1 kináz számos központi idegrendszeri megbetegedéssel kapcsolatba hozható, és fontos szerepet játszik a gyulladásos folyamatok szabályozásában. A fehérje gátlásával potenciálisan csökkenthető a gyulladás mértéke. Munkánk során egy referenciavegyületből kiindulva, alapváz-helyettesítéses módszerrel új, aktív szerkezeti kört azonosítottunk. Szisztematikus gyógyszerkémiai optimalizációval, ideális szubsztituensek megválasztásával sikerült egy in vitro méréseken aktív, szelektív RIP1 kináz gátlót szintetizálnunk. | Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) plays a critical role in regulating cell death and inflammation, making it an important therapeutic target in various diseases, including neurodegenerative disorders. RIPK1 is a central mediator of both necroptosis (regulated necrosis) and apoptosis, acting as a switch between cell survival and death. RIPK1 is characterized by a unique allosteric pocket that regulates its kinase activity, making it a promising target for selective inhibition. The discovery of small molecules capable of modulating this allosteric site offers the potential for highly specific inhibitors, a key advantage for therapeutic intervention. In particular, the unique kinase-regulating allosteric pocket allows for the development of compounds that can selectively inhibit RIPK1 without interfering with other kinases that share similar structural features. In our discovery campaign, we initially focused on GSK2982772 as a starting point for the design of RIPK1 inhibitors. We applied scaffold hopping strategy to explore alternative scaffolds that could retain the binding affinity and selectivity for RIPK1 while offering improved pharmacological properties. Through this approach, we successfully identified the malonamide scaffold as a suitable replacement for the well-established serine template found in previous RIPK1 inhibitors. The malonamide scaffold offered a favorable binding profile within the allosteric pocket of RIPK1, presenting an opportunity to enhance the compound’s potency and selectivity. This scaffold was further optimized to create a series of analogs, each with variations in their chemical structures designed to improve affinity for RIPK1. Once the analogs were synthesized, we tested the enantiomers of the most promising compound on a panel of 97 different kinases. The goal was to assess the compound’s selectivity across a wide range of kinases, ensuring that the active enantiomer would exhibit a high degree of specificity for RIPK1 while avoiding undesirable interactions with other kinases that could lead to side effects. The results of these kinase assays demonstrated that the active enantiomer of the compound was indeed highly selective for RIPK1, confirming the success of the isosteric replacement strategy and the potential of the malonamide scaffold as a platform for developing selective RIPK1 inhibitors. This work highlights the effectiveness of scaffold replacement and structural optimization in the design of selective kinase inhibitors. By focusing on the unique allosteric pocket of RIPK1 and applying a systematic approach to scaffold modification, we were able to develop a highly selective and potent inhibitor of RIPK1.

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