Discovery of quinazoline derivatives as RIPK3 inhibitors that switch cell death from necroptosis to apoptosis for psoriasis treatment

Abstract

In this study, we employed a structure-based approach and step-by-step structural optimization to identify a series of quinazoline derivatives as potent receptor interacting protein kinase 3 (RIPK3) inhibitors. Among these, compound 32 emerged as the most effective inhibitor, with strong inhibition of RIPK3 (IC₅₀ = 27 nM) and necroptosis (EC₅₀ = 0.45 μM). Biological evaluation showed that compound 32 binds directly to RIPK3, inhibiting the phosphorylation of both RIPK3 and its downstream substrate, MLKL, thus suppressing necroptosis. Additionally, compound 32 induces Caspase-8/3-mediated apoptosis, resulting in moderate anti-proliferative effects. By converting inflammatory necroptosis to non-inflammatory apoptosis, compound 32 not only exerts anti-inflammatory effects but also reduces inflammatory hyperplasia. More importantly, compared to the known RIPK3 inhibitor HS-1371, compound 32 significantly lower toxicity in vivo in mice. In an IMQ-induced mouse model of psoriasis, compound 32 significantly alleviates skin inflammation, scaling, and hyperkeratosis, without inducing notable toxicity. This study highlights a promising therapeutic strategy for inflammatory proliferative diseases, such as psoriasis, by inhibiting RIPK3 and shifting the mode of cell death from necroptosis to apoptosis.