This study identifies and characterizes compound 24 (HA-218-6-31-80), a novel small-molecule NEDD8-activating enzyme (NAE) inhibitor. Discovered from a high-throughput screening, followed by structure-guided optimization, compound 24 possesses a distinct spirocyclic amide chemical core entirely different from the clinical-stage NAE inhibitor MLN4924. Biochemical assays confirm that compound 24 directly binds NAE and suppresses its catalytic activity, blocks the formation of E2-NEDD8 thioesters, and reduces the neddylation of CUL1 and CUL5 in purified protein systems. In human lung cancer cells, it potently suppresses neddylation of multiple CUL family members, leading to the accumulation of CRL substrates including p27 and NOXA. Functionally, it triggers G1-phase arrest and NOXA-dependent apoptosis, inhibiting lung cancer cell proliferation and survival. In A549 xenograft models, it significantly suppresses tumor growth without obvious systemic toxicity. Collectively, 24 (HA-218-6-31-80) represents a promising NAE inhibitor, offering a potential therapeutic candidate for lung cancer and a novel scaffold for neddylation targeted drug discovery.
MDM2 is an oncogenic E3 ubiquitin ligase best known for targeting the tumor suppressor p53 and is frequently amplified in human cancers, including dedifferentiated liposarcoma (DDLPS). We show that supraphysiological MDM2 expression can be exploited to reprogram its ligase activity toward selective degradation of oncogenic transcriptional machinery. Using a substrate substitution strategy, we developed an MDM2-recruiting degrader dCDK9-010 that targets positive transcription elongation factor b, inducing its proteasomal degradation while simultaneously stabilizing p53. This dual action disrupts RNA polymerase II abundance and elongation, preferentially impairing enhancer-driven transcriptional programs that sustain tumor growth. In DDLPS models, this approach produces potent antitumor activity with favorable pharmacokinetic and safety profiles, triggers apoptosis, and enhances macrophage-mediated tumor cell clearance. These findings establish substrate substitution-based reprogramming of MDM2 as a generalizable targeted protein degradation strategy and identify
MDM2
amplification as a predictive biomarker for therapeutic response across cancer types, with particular relevance to liposarcoma.
Ye Chen, Long Xie, Xian Guan et al.· Cell Death & Disease· 0 citations
