Profiling of small‐molecule necroptosis inhibitors based on the subpockets of kinase–ligand interactions

Abstract

Necroptosis is a highly regulated cell death (RCD) form in various inflammatory diseases. Receptor‐interacting protein kinase 1 (RIPK1) and RIPK3 are involved in the pathway. Targeting the kinase domains of RIPK1 and/or 3 is a drug design strategy for related diseases. It is generally accepted that essential reoccurring features are observed across the human kinase domains, including RIPK1 and RIPK3. They present common N‐ and C‐terminal domains that are built up mostly by α‐helices and β‐sheets, respectively. The current RIPK1/3 kinase inhibitors mainly interact with the kinase catalytic cleft. This article aims to present an in‐depth profiling for ligand–kinase interactions in the crucial cleft areas by carefully aligning the kinase‐ligand cocrystal complexes or molecular docking models. The similarity and differential structural segments of ligands are systematically evaluated. New insights on the adaption of the conserved and selective kinase domains to the diversity of chemical scaffolds are also provided. In a word, our analysis can provide a better structural requirement for RIPK1 and RIPK3 inhibition and a guide for inhibitor discovery and optimization of their potency and selectivity.

Insight from Linker Investigations: Discovery of a Novel Phenylbenzothiazole Necroptosis Inhibitor Targeting Receptor-Interacting Protein Kinase 1 (RIPK1) from a Phenoxybenzothiazole Compound with Dual RIPK1/3 Targeting Activity

“…The design of selective kinase inhibitors poses a constant challenge due to the significant similarity of the kinase binding pockets . Considering the therapeutic relevance, biological understanding, and safety advantages of RIPK1 mentioned in Section , designing selective RIPK1 inhibitors may achieve better clinical efficacy and development prospects than RIPK3 or RIPK1/RIPK3 dual inhibitors. ,,− For the rationale, we have deeply analyzed that the first three residues of activation loop (DLG) of RIPK1 differs from other RIPK members, which typically have DFG motifs . The above result emphasizes the significance of the linker region in determining the impact of selectivity and activity on compounds.…”

“…A heteroaryl compound DNL758/SAR443122 was initiated by Denali and Sanofi to conduct a clinical trial on cutaneous lupus erythematosus (CLE) patients (JXHL2200324, JXHL2200325). Additionally, various potent RIPK1 inhibitors reported by different research groups − and comprehensive reviews are available for reference. ,, …”

“…Given the integral role of the necroptosis pathway in the development of various diseases, there is significant therapeutic potential in targeting this pathological process. ,, So far, RIPK1, RIPK3, and MLKL have been acknowledged as crucial therapeutic targets in the process of necroptosis . Especially, RIPK1 plays a crucial role in inflammatory diseases, autoimmune conditions, and neurodegenerative disorders .…”

Artificial Peptide‐Protein Necrosomes Promote Cell Death

“…[49] Thus far, a considerable number of organic or inorganic compounds or materials have been developed to promote the necroptotic pathway in tumor cells for cancer therapy. [50][51][52] Despite availability of a few inhibitors that directly target RIPK3, [53] these compounds and materials typically activate necroptosis indirectly by interacting with RIPK3 due to the lack of an agonistic mechanism for RIPK3. This has led to the recognition of RIPK3 as an "undruggable" target for necroptosis.…”

“…For preliminary solution studies, we simultaneously designed a RIPK3-biomimetic peptide, PR3 (NIYNCSGVQVGD), derived from its RHIM motif and known to undergo robust Hbonding interaction with RIPK1, as previously revealed. [53] Furthermore, due to the proteolytic resistance of D -peptide bonds, D -peptides have been broadly synthesized as alternatives to natural peptides. Co-assembly of D -peptides with their L -counterparts might also facilitate formation of nanostructures stabilized by parallel rippled β-sheet interactions.…”