DJ-1-IN-1

DJ-1-IN-1 is a small molecule inhibitor of DJ-1 (also known as PARK7), a protein that plays a critical role in regulating cell survival and suppressing necroptosis. In the context of FLT3-ITD acute myeloid leukemia (AML), DJ-1 has been identified as a survival regulator that maintains resistance to necroptotic cell death by sustaining the expression of TNFAIP3 (A20) and modulating RIPK1 ubiquitin signaling. Pharmacologic inhibition of DJ-1 using DJ-1-IN-1 selectively enhances necroptosis in AML cells, as evidenced by the increased phosphorylation of RIPK1, RIPK3, and MLKL, along with enhanced membrane damage. Preclinical studies in murine MLL-AF9 AML models have demonstrated that treatment with DJ-1-IN-1 significantly delays leukemia progression, suggesting that targeting the DJ-1–TNFAIP3–RIPK1 axis represents a novel therapeutic vulnerability in high-risk AML.