Small-Molecule Receptor-Interacting Protein 1 (RIP1) Inhibitors as Therapeutic Agents for Multifaceted Diseases: Current Medicinal Chemistry Insights and Emerging Opportunities

Abstract

As a serine/threonine protein kinase, receptor-interacting protein 1 (RIP1) plays an important role in regulating the pathways in programmed cell death. Multifaceted human diseases (e.g., autoimmune diseases, inflammatory diseases, neurodegenerative diseases, and tumors) are closely related to RIP1 kinase. Therefore, small-molecule RIP1 inhibitors with precise targeting and good penetrability have recently been used in potentially therapeutic methods, attracting extensive researcher interest. GSK2982772, developed by GlaxoSmithKline (GSK), became the world’s first RIP1 inhibitor approved for clinical research in 2014. Nine clinical trials assessing GSK2982772 have been performed. The most recent direction in RIP1 inhibitor development has been focused on RIP1 small-molecule inhibitors with higher potency, selectivity, and metabolic stability. In this Perspective, considering the structure, biological functions, and disease relevance of RIP1, we summarize the recent research progress in RIP1 small-molecule inhibitor development based on different binding modalities and discuss prospective strategies for designing additional RIP1 therapeutic agents.

From PERK to RIPK1: Design, synthesis and evaluation of novel potent and selective necroptosis inhibitors

“…Compound 30 with Frontiers in Chemistry frontiersin.org fluorine is the most potent compound of the entire series (IC 50 = 0.01 nM), with 40-fold higher potency than GSK'157. To the best of our knowledge, this is the most potent necroptosis inhibitor ever reported (Martens et al, 2020;Chen et al, 2022;Shi et al, 2022). However, compared to the corresponding pyridinyl analogues (18-20), the phenyl analogues 30-32 retained some PERK inhibition, albeit at concentration higher than 1 µM which still results in excellent selectivity.…”

“…Particularly, the co-crystallization of Nec-1s, a stable form of Nec-1, with the kinase domain of RIPK1 demonstrated the typical type III kinases inhibitor mode of interaction, with binding to the specific RIPK1 allosteric pocket formed by the DLG-out conformation and without interacting with the hinge region (Wang et al, 2006;Zheng et al, 2008;Takahashi et al, 2012). Since then, several additional RIPK1 inhibitors have been reported (Martens et al, 2020;Chen et al, 2022;Shi et al, 2022). Among them, a class of compounds featuring a benzoxazepinone core emerged with GSK2882481 (Clark et al, 2009;Harris et al, 2016), but interspecies differences were observed when comparing humans to non-primate RIPK1, probably due to the different amino acids featured by the enzyme affecting protein flexibility (Berger et al, 2015;Harris et al, 2017).…”

“…Among the different RIPK1-inhibitors available in the literature (Figure 1), the type II class has been less investigated in disease models and in clinic (Martens et al, 2020;Chen et al, 2022;Shi et al, 2022). In the type II RIPK1 inhibitors family, tyrosine kinase inhibitor (TKI) ponatinib and its analogues, and sorafenib are reported as dual inhibitors for both RIPK1 and RIPK3 (Fauster et al, 2015;Martens et al, 2017).…”

From (Tool)Bench to Bedside: The Potential of Necroptosis Inhibitors

“…The reader is directed to another review for further details on these recently identified scaffolds. 142 4.2. Inhibitors of RIPK3.…”

“…Various other inhibitors of RIPK1 have been identified (structures not shown); however, as many of these compounds were developed as inhibitors of other kinases or are hits from library screens without optimization, these scaffolds primarily serve as a demonstration of the increasing efforts being directed toward the discovery and development of RIPK1 inhibitors as therapeutics. The reader is directed to another review for further details on these recently identified scaffolds …”