Juq-123

JUQ-123: A Novel Dual Inhibitor Targeting JAK2 and USP7 Demonstrates Synergistic Anti-Tumor Efficacy in Preclinical Models of Acute Myeloid Leukemia

Abstract Background: Acute Myeloid Leukemia (AML) remains a hematological malignancy with poor prognosis, particularly in patients with high-risk genetic mutations. Constitutive activation of the JAK-STAT pathway and the dysregulation of deubiquitinases (DUBs), specifically USP7, are two critical mechanisms driving AML pathogenesis and chemoresistance. Methods: We describe the preclinical characterization of JUQ-123, a first-in-class, rationally designed small molecule that acts as a dual inhibitor of JAK2 and USP7. In vitro assays were conducted to evaluate binding affinity, kinase selectivity, and DUB inhibitory activity. Cellular proliferation, apoptosis, and cell cycle analyses were performed on a panel of AML cell lines and primary patient-derived xenograft (PDX) cells. In vivo efficacy was assessed using systemic AML murine models. Results: JUQ-123 exhibited high affinity for both the ATP-binding pocket of JAK2 (IC50 = 12 nM) and the catalytic domain of USP7 (IC50 = 35 nM). In AML cell lines, JUQ-123 induced robust G1 cell cycle arrest and apoptosis, outperforming monotherapies targeting either JAK2 (Ruxolitinib) or USP7 (FTX-671) alone. Mechanistically, dual inhibition resulted in the concurrent suppression of STAT5 phosphorylation and the stabilization of the tumor suppressor p53. In vivo, oral administration of JUQ-123 led to significant leukemic burden reduction and prolonged overall survival without inducing systemic toxicities. Conclusions: JUQ-123 represents a highly promising therapeutic strategy. By simultaneously disrupting JAK-STAT signaling and restoring p53 tumor suppressor activity via USP7 inhibition, JUQ-123 circumvents compensatory resistance mechanisms, warranting its rapid translation into early-phase clinical trials for high-risk AML.

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Electronic structure analysis shows a wide bandgap of 3.1 eV, consistent with the observed low leakage currents. JUQ-123: A Novel Dual Inhibitor Targeting JAK2 and

Concurrently, Ubiquitin-Specific Protease 7 (USP7) has emerged as a critical regulator of AML cell survival. USP7 deubiquitinates and stabilizes oncogenic proteins such as N-Myc and Tip60, while conversely targeting the tumor suppressor p53 for proteasomal degradation. Preclinical USP7 inhibitors induce apoptosis in AML, but their efficacy is often blunted by persistent upstream proliferative signaling. In vitro assays were conducted to evaluate binding