Juq-123 - |work|

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.

4. Getting Started – A Quick Setup Guide

1. Unbox & Power Up – Plug the AC adapter (or connect via PoE) and let the hub boot (≈ 45 seconds).
2. Download the JUQ‑App – Available for iOS, Android, and desktop.
3. Create/Link Account – Optional cloud sync; you can skip this for a fully offline experience.
4. Add Devices – The app automatically discovers Matter‑compatible devices. For legacy Zigbee/Thread devices, just press “Add Legacy Device” and follow the on‑screen prompts.
5. Configure Routines – Use the visual flow builder to set up automations (e.g., “If motion detected after 10 pm → turn on hallway light at 30 %”).
6. Explore Modules – Visit the JUQ‑Marketplace, install a few modules that suit your lifestyle, and watch the hub expand its capabilities.

That’s it—JUQ‑123 is ready to become the heart of your smart home. JUQ-123

3.1. Crystal Structure

JUQ‑123 crystallizes in the orthorhombic Pna2₁ space group (a = 9.832 Å, b = 12.415 Å, c = 7.658 Å, Z = 4). The structure comprises ZrO₆ octahedra linked by the APQ ligands forming a 3‑D framework (Fig. 1a). The quinoxaline cores adopt a head‑to‑tail arrangement, generating a permanent dipole along the c‑axis. Hydrogen‑bonded NH₃⁺ groups bridge neighboring octahedra, establishing a proton‑transfer network (Fig. 1b). JUQ-123: A Novel Dual Inhibitor Targeting JAK2 and

SHG measurements confirm the non‑centrosymmetric nature, yielding a signal 0.12 × KDP, comparable to known ferroelectrics. Unbox & Power Up – Plug the AC

a. Universal Compatibility (Matter + Legacy)

JUQ‑123 is the first hub to natively support the Matter standard and retain full backward compatibility with older Zigbee and Thread devices. This means you can keep your existing smart bulbs, sensors, and locks without any extra adapters.