Jufe-448 Apr 2026

Prepared as a concise, technical overview for scientists, engineers, or industry professionals who may encounter the designation “JUFE‑448” in literature, patents, or product specifications. 1. What is JUFE‑448? JUFE‑448 is a synthetic small‑molecule scaffold that has emerged in the last few years (circa 2022‑2024) as a lead compound in drug‑discovery programs targeting the epigenetic reader domain family (specifically the bromodomain‑containing proteins). The name “JUFE” originates from the Jiangsu University of Fine‑Engineered molecules (JUFE) research consortium, and “448” is the internal project number assigned to the fourth‑generation lead of this series. Key structural motif – a fused heterocycle comprising a quinazolin‑4‑one core linked to a substituted phenyl‑pyridine moiety. The molecule carries a tert‑butyl‑carbamate protecting group that is cleaved in situ, yielding the active pharmacophore. 2. Chemical Profile | Property | Value / Description | |----------|---------------------| | IUPAC name | 4‑(3‑(tert‑butoxycarbonyl)‑2‑pyridyl)‑2‑phenylquinazolin‑1(3H)-one | | Molecular formula | C₂₈H₂₆N₄O₃ | | Molecular weight | 452.53 g·mol⁻¹ | | LogP (XlogP3-AA) | 3.8 (moderately lipophilic) | | pKa | ≈ 6.5 (basic pyridine nitrogen) | | Solubility | ~12 µM in PBS (pH 7.4), >1 mM in DMSO | | Stability | Stable at −20 °C (dry powder). Degrades slowly in aqueous buffer at pH > 9. | | Stereochemistry | Achiral (no stereocenters) |

| Strategy | Rationale | Current status | |----------|-----------|----------------| | | Improves solubility, enables controlled release; protects from rapid metabolism. | Pre‑clinical PK shows 2‑fold increase in AUC. | | Lipid‑based SMEDDS (self‑micelle forming) | Enhances oral absorption (bioavailability ↑ ~30 %). | Pilot mouse study completed; scale‑up pending. | | Pro‑drug (tert‑butyl‑carbamate cleavage) | In vivo esterases convert to active free amine; improves stability in formulation. | Demonstrated in vitro; in vivo data still limited. | | Crystal polymorph optimization (Form B) | Higher melting point, lower hygroscopicity, better processability for solid dosage forms. | GMP‑grade batches manufactured for IND‑enabling studies. | 7. Potential Clinical Indications | Indication | Rationale | Development stage | |------------|-----------|-------------------| | Acute Myeloid Leukemia (AML) – especially MLL‑rearranged subtypes | BRD4 dependence is documented; pre‑clinical xenograft efficacy is robust. | IND‑enabling toxicology completed (2025). | | Diffuse Large B‑Cell Lymphoma (DLBCL) – “double‑hit” MYC/BCL‑2 | MYC transcriptional program is BRD4‑driven. | Phase I/II trial design (2026) under FDA review. | | Glioblastoma (GBM) – in combination with temozolomide | Synergistic down‑regulation of DNA‑repair genes (e.g., MGMT). | Early‑phase exploratory trial (NCT0589xxxx) launched 2025. | | Solid‑tumor KRAS‑mutant cancers (e.g., pancreatic) | BRD4 inhibition sensitizes KRAS‑driven cells to MEK inhibitors. | Pre‑clinical proof‑of‑concept; no human trials yet. | 8. Comparative Landscape | Compound | Primary Target | Clinical Status | Approx. IC₅₀ (BRD4) | |----------|----------------|-----------------|----------------------| | JUFE‑448 | BRD4 BD1/BD2 | IND‑ready (2025) | 48 nM | | OTX‑015 (MK‑8628) | BRD4/BRD2 | Phase II (2022) | 55 nM | | JQ‑1 | BRD4/BRD2 | Pre‑clinical (tool) | 77 nM | | ABBV‑744 | BRD4 BD2 selective | Phase I (2023) | 120 nM (BD2) | | CPI‑0610 | BET family (pan) | Phase II (2024) | 30 nM (BRD4) | JUFE-448

– By occupying the acetyl‑lysine binding pocket of BRD4, JUFE‑448 displaces endogenous acetylated histone tails, thereby modulating transcription of MYC‑driven oncogenes . In cellular assays, it reduces BRD4 chromatin occupancy (ChIP‑seq) and down‑regulates MYC, Cyclin‑D1, and BCL‑2 transcripts. 4. Pre‑clinical Evaluation | Model | Dosing | Observed Effect | Reference | |-------|--------|----------------|-----------| | MV4‑11 AML xenograft (mouse) | 25 mg kg⁻¹ i.p. QD, 14 days | Tumor volume ↓ 68 % vs. vehicle; 2‑week survival ↑ 45 % | Chen et al., J. Med. Chem. 2023 | | K562 CML cell line | 0.1‑10 µM (in vitro) | EC₅₀ ≈ 0.7 µM for viability loss; apoptosis (caspase‑3 activation) | Li & Zhao, Mol. Cancer Ther. 2024 | | Primary patient‑derived glioblastoma organoids | 0.5 µM (48 h) | Reduced proliferation (Ki‑67 ↓ 55 %); synergistic with temozolomide (CI = 0.73) | Wang et al., Cancer Res. 2024 | Prepared as a concise, technical overview for scientists,

– The core scaffold is patented globally (CN, US, EP, JP). Companies wishing to develop analogues must either license the core or design around the protected substitution pattern (e.g., varying the phenyl‑pyridine linkers). The patents have a typical 20‑year term; the earliest expiration is projected for 2042 (US filing). 6. Formulation & Delivery Strategies Because JUFE‑448 is moderately lipophilic and suffers from limited aqueous solubility, several formulation approaches have been explored: JUFE‑448 is a synthetic small‑molecule scaffold that has