1. Product Overview
Emavusertib hydrochloride (CAS No. 2376399-42-5), also known as CA-4948 hydrochloride, is the hydrochloride salt form of Emavusertib (free base: HY-135317). With molecular formula C24H26ClN7O5 and MW 527.96 g/mol, it is an orally bioavailable, potent, and selective dual inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4, IC50 = 57 nM) and FMS-like tyrosine kinase 3 (FLT3). By blocking IRAK4 within the MyD88-dependent TLR/IL-1R signaling axis, it suppresses NF-κB activation and reduces pro-inflammatory cytokines (IL-6, IL-10), while concurrently inhibiting FLT3-driven survival signals in acute myeloid leukemia (AML) and B-cell lymphoma models. Originally developed by Curis/Boehringer Ingelheim and advanced to Phase I/II trials (emavusertib, CA-4948) for relapsed/refractory AML, MDS, and ABC-DLBCL, it serves as a key pharmacological probe for innate immune signaling dissection, IRAK4-FLT3 co-targeting, and overcoming resistance to BTK/PI3K inhibitors in lymphoid malignancies.
2. Key Features and Advantages
• Dual IRAK4/FLT3 Blockade: IRAK4 IC50 = 57 nM; potent FLT3 inhibition (IC50 in low-nanomolar range); >100-fold selectivity over a broad kinase panel including IRAK1/2, TBK1, and unrelated serine/threonine/tyrosine kinases.
• Suppresses MyD88 Signaling: Disrupts IRAK4–MyD88 complex formation, blocks NF-κB and MAPK pathway activation, and reduces IL-6/IL-10 production in MyD88-mutant ABC-DLBCL and AML cell lines.
• In Vivo Antitumor Activity: Oral dosing (30–100 mg/kg) achieves tumor regression in AML PDX, ABC-DLBCL xenografts, and mouse models with secondary resistance to BTK/PI3K inhibitors; improves survival in systemic lupus erythematosus (SLE) models.
• Hydrochloride Salt Form: Enhanced aqueous solubility vs free base; suitable for both cell culture (DMSO stock ≤0.1%) and in vivo formulation in saline or vehicle.
• Research-Grade Quality: ≥98% purity (HPLC), white to off-white solid, stable powder at -20°C for 2–3 years; MW 527.96, formula C24H25N7O5·HCl.
3. Main Applications
• Hematologic Malignancy Research: AML, MDS, ABC-DLBCL, and Waldenström macroglobulinemia models driven by MyD88 mutations or FLT3-ITD; evaluating IRAK4/FLT3 co-targeting vs single-agent BTK/PI3K blockade.
• Innate Immune Signaling Dissection: Studying TLR/IL-1R–MyD88–IRAK4 axis in macrophages, dendritic cells, and B/T lymphocytes; monitoring pIRAK4, pIKK, pNF-κB, and cytokine secretion upon inhibition.
• Resistance Mechanism Studies: Overcoming secondary resistance to ibrutinib (BTK inhibitor) or duvelisib (PI3Kδ/γ) in CLL/DLBCL by adding emavusertib to restore T-cell immunity and block MyD88 survival signals.
• Drug Combination Screens: Synergy with venetoclax (BCL2), azacitidine/decitabine (hypomethylating agents), PD-1/PD-L1 checkpoint blockade, or KRAS/MAPK pathway inhibitors in myeloid/lymphoid contexts.
• Clinical-Stage Reference: Phase I/II agent (NCT05075327, NCT03328078); serves as benchmark IRAK4 inhibitor alongside PF-06650833 and zimlovisertib (PF-06650897) for degrader design (IRAK4 PROTACs).
4. Technical Specifications
5. Storage and Handling
Store powder at -20°C in a tightly sealed, desiccated container protected from light; stable for 2–3 years. Prepare DMSO stock at 10–25 mg/mL with brief sonication and warming to 37 °C; aliquot to avoid freeze-thaw and store at -80°C up to 6 months or -20°C up to 1 month. As hydrochloride salt, it has improved aqueous solubility—can be dissolved directly in PBS or saline at 1–5 mg/mL for in vivo IP/IV dosing; for oral gavage use 10% DMSO + 90% saline or 0.5% methylcellulose. Allow vial to reach room temperature before opening; weigh in fume hood with nitrile gloves and goggles.
6. Safety Overview
For laboratory research use only, not for human/veterinary therapeutic or diagnostic use. GHS07 possible (H302 harmful if swallowed, H315/H319 skin/eye irritant). Handle as bioactive kinase/IRAK4 inhibitor with immunomodulatory effects; wear nitrile gloves, goggles, lab coat; avoid dust inhalation and skin contact. Dispose as organic chemical waste per local regulations. Include DMSO/saline vehicle controls in all cell, primary immune cell, and animal assays.
