1. Product Overview
CD38 inhibitor 1, also known as Compound 78c or MDK-7553 (CAS No. 1700637-55-3), is a potent, orally bioavailable, small-molecule inhibitor of cluster of differentiation 38 (CD38), a transmembrane ectoenzyme with ADP-ribosyl cyclase and NAD+ glycohydrolase activity. With molecular formula C22H27N3O3S and MW 413.53 g/mol, it blocks human and mouse CD38 with IC50 values of 7.3 nM and 1.9 nM respectively in cell-free assays. By inhibiting CD38-mediated NAD+ hydrolysis, it elevates intracellular NAD+ levels in liver and muscle tissues after oral dosing (30 mg/kg), restores NAD-dependent SIRT1 activity, and modulates immune cell function. Originally reported by Haffner et al. (J Med Chem 2015), it serves as a key pharmacological tool for studying NAD metabolism, aging, metabolic disorders, and CD38-dependent pathways in multiple myeloma and lymphoid malignancies where CD38 is highly overexpressed.
2. Key Features and Advantages
• Potent CD38 Blockade: IC50 = 7.3 nM (human CD38), 1.9 nM (mouse CD38); >100-fold selectivity over related NAD-processing enzymes (ARTs, PARG, SARM1) and broad kinase panel.
• Elevates Intracellular NAD+: Oral dosing at 30 mg/kg significantly increases NAD levels in liver and skeletal muscle within 2–6 hours in DIO mice; restores SIRT1 deacetylase activity linked to metabolic health.
• Orally Bioavailable: Good PK profile in rodents; suitable for chronic in vivo studies on aging, NAD decline, and metabolic disease models.
• Defined Quinolinone Scaffold: 4-[[trans-4-(2-Methoxyethoxy)cyclohexyl]amino]-1-methyl-6-(thiazol-5-yl)quinolin-2(1H)-one core; trans-cyclohexyl and thiazole motifs enable SAR around CD38 pocket.
• Research-Grade Quality: ≥98% purity (HPLC), light yellow to brown solid, stable at -20°C for 2–3 years; soluble in DMSO (>25 mg/mL, sonication + 60 °C warming recommended).
3. Main Applications
• NAD Metabolism & Aging Research: Probing CD38 as the primary NADase in mammalian tissues; studying NAD decline during aging and restoration via CD38 inhibition in liver, muscle, and brain.
• Multiple Myeloma & Hematologic Malignancies: CD38 is a canonical target in MM (daratumumab/isatuximab target antigen); using Compound 78c to dissect CD38 enzymatic vs epitope roles, and combine with IMiDs or BCL2 inhibitors.
• Immunometabolism: Modulating T-cell, NK-cell, and macrophage NAD pools; evaluating CD38 inhibitor effects on cytokine production (IL-6, TNF-α) and immune cell exhaustion.
• Metabolic Disease Models: DIO mice, senescence-accelerated mouse models (SAMP8), and high-fat-diet studies to assess CD38 blockade on insulin sensitivity, mitochondrial function, and SIRT1/SIRT3 activity.
• Drug Discovery Reference: Serves as lead CD38 inhibitor for PROTAC design (CD38 degraders), analog optimization (e.g., newer clinical candidates like ipatasertib-related CD38 modulators), and comparator in NADase assay development.
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 sonication and gentle warming to 60 °C to fully dissolve (quinolinone core can be slow to solubilize at RT); aliquot to avoid freeze-thaw and store at -80°C up to 6 months or -20°C up to 1 month. For in vivo oral gavage, formulate in 10% DMSO with 90% saline or 0.5% methylcellulose; sonicate to clarity at 1–5 mg/mL. Allow vial to reach room temperature before opening; weigh in fume hood with nitrile gloves and goggles. The compound is light-sensitive—keep solutions and powder protected from light during handling.
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 small molecule affecting NAD metabolism and immune function; 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 (DIO/SAMP8) assays.
