1. Product Overview
IMT1B (CAS 2304621-06-3), also known as LDC203974, is a potent, orally active, and specific allosteric inhibitor of human mitochondrial RNA polymerase (POLRMT). With the molecular formula C₂₄H₂₁ClFNO₆ and a molecular weight of 473.88 g/mol, this complex chiral molecule features a chromen-7-yloxy propanoyl-piperidine-3-carboxylic acid architecture. IMT1B binds to the non-canonical pocket of POLRMT (Kd = 2.3 μM), inducing a distinct allosteric conformation that impairs mitochondrial transcription and OXPHOS protein synthesis, leading to cellular energy crisis and broad-spectrum anticancer effects. It is a valuable tool compound for studying mitochondrial biology, metabolic reprogramming, and cancer therapeutics.
2. Key Features and Benefits
• Highly Specific Allosteric Inhibition: Targets the non-canonical pocket of POLRMT with Kd = 2.3 μM, inducing a unique allosteric conformation that selectively disrupts mitochondrial transcription without affecting nuclear RNA polymerases.
• Broad Anticancer Activity: Inhibits cell proliferation across a wide panel of cancer cell lines with IC₅₀ values in the low micromolar range; particularly effective in cancer cells with high mitochondrial dependence.
• Oral Bioavailability: Demonstrates good pharmacokinetic properties suitable for in vivo studies, with measurable tumor growth inhibition in xenograft models.
• Dual Stereochemistry: The (3S,2R) configuration is critical for POLRMT binding affinity and allosteric induction; high enantiomeric purity ensures reproducible biological activity.
• Mitochondrial Selectivity: Selectively targets mitochondrial gene expression with minimal impact on nuclear DNA transcription, making it a precise tool for dissecting mitochondrial vs. nuclear contributions to cellular metabolism.
3. Major Applications
• Cancer Biology & Drug Discovery: Used to probe mitochondrial vulnerability in cancer cells, particularly in models of glioblastoma, breast cancer, lung cancer, and other malignancies with high oxidative phosphorylation (OXPHOS) dependence.
• Mitochondrial Research: Serves as a chemical probe to study mitochondrial transcription regulation, mtDNA expression, and the role of POLRMT in cellular metabolism and aging.
• Metabolic Reprogramming Studies: Employed to investigate the metabolic shift between glycolysis and OXPHOS in cancer cells, and to identify synthetic lethal interactions with mitochondrial dysfunction.
• In Vivo Xenograft Models: Administered orally or intraperitoneally to evaluate antitumor efficacy, pharmacodynamics (PD) markers (e.g., mtDNA-encoded protein levels), and pharmacokinetics (PK) in mouse models.
• High-Throughput Screening: Used as a reference standard or tool compound in screening campaigns to identify additional POLRMT inhibitors or compounds with synthetic lethal interactions.
4. Technical Specifications
Item Description
Product Name IMT1B (LDC203974)
Synonyms LDC203974; (S)-1-((R)-2-((4-(2-Chloro-4-fluorophenyl)-2-oxo-2H-chromen-7-yl)oxy)propanoyl)piperidine-3-carboxylic acid; (3S)-1-[(2R)-2-{[4-(2-Chloro-4-fluorophenyl)-2-oxo-2H-chromen-7-yl]oxy}propanoyl]-3-piperidinecarboxylic acid
CAS Number 2304621-06-3
Molecular Formula C₂₄H₂₁ClFNO₆
Molecular Weight 473.88 g/mol
MDL Number —
Assay (Purity) ≥95% / ≥98% (HPLC)
Enantiomeric Purity ≥99% ee
Appearance White to off-white crystalline solid or powder
Boiling Point ~705.7 °C (Predicted)
Density ~1.426 g/cm³ (Predicted)
pKa (Predicted) 4.33 ± 0.20 (Carboxylic acid)
Calculated LogP ~3.7
Polar Surface Area (PSA) ~93.1 Ų
Hydrogen Bond Donors 1
Hydrogen Bond Acceptors 7
Rotatable Bonds 5
Solubility Soluble: DMSO (>50 mg/mL, sonication recommended), 0.1N NaOH (aq), Ethanol (slightly).
Slightly Soluble:Water (free acid form, pH-dependent; more soluble as sodium/potassium salt).
Insoluble:Hexane, Ether.
Spectral Data (Predicted) ¹H NMR (DMSO‑d₆, 400 MHz): δ 1.25 (d, J≈7.0 Hz, 3H, CH₃), 1.55–2.85 (m, 6H, piperidine-CH₂), 4.55–4.85 (m, 1H, CHO), 6.80–7.60 (m, 7H, aromatic H), 10.5 (br s, 1H, COOH), 12.8 (br s, 1H, chromen-2-one NH).
¹³C NMR (DMSO‑d₆):δ 18.5 (CH₃), 28–55 (piperidine Cs), 75.5 (CHO), 110–165 (aromatic + chromenone Cs), 165.0 (C=O), 172.0 (COOH), 178.5 (chromenone C=O).
SMILES ClC1=C(F)C=CC(=C1)C2=CC(=O)OC3=C2C=C(OC(C)C(=O)N4CCCC(C4)C(=O)O)C=C3
InChI Key PFEKWBKJUBCXDT-KGLIPLIRSA-N
Storage (Powder) -20°C, protected from light and moisture; stable ≥2–3 years
Solution Stability DMSO stocks stable at -20°C for 1–3 months; avoid repeated freeze-thaw; working dilutions should be used within 24 h
HS Code 2932.99.90 / 2934.99.90
5. Storage and Handling
• Powder Storage: Store sealed vial at -20°C (or -80°C for long-term), protected from light in a desiccated environment. Stable for at least 24 months from date of manufacture.
• Stock Solution: Dissolve in anhydrous DMSO to 10–20 mM (4–8 mg/mL). Warm briefly to 37°C and vortex; sonication may aid complete dissolution. Protect from light.
• Working Dilution: Dilute into cell culture medium immediately before use. Final DMSO concentration in assays should not exceed 0.1% (v/v). For in vivo studies, prepare fresh suspension in vehicle (e.g., 5% DMSO + 95% corn oil or 0.5% carboxymethyl cellulose (CMC) in saline).
• Freeze-Thaw: Aliquot DMSO stocks upon preparation. Minimize freeze-thaw cycles; discard any precipitated or discolored solution.
6. Safety Summary (Full SDS Highlights)
• GHS Classification: GHS07 – Warning
• Signal Word: Warning
• Hazard Statements:
• H302: Harmful if swallowed.
• H312: Harmful in contact with skin.
• H315: Causes skin irritation.
• H319: Causes serious eye irritation.
• H335: May cause respiratory irritation.
• H351: Suspected of causing cancer (based on structural alerts—handle with caution).
• Precautionary Statements:
• P201: Obtain special instructions before use.
• P261: Avoid breathing dust/mist/vapors. Use only in a well-ventilated area or fume hood.
• P264: Wash hands, forearms, and face thoroughly after handling.
• P270: Do not eat, drink, or smoke in areas where this material is used.
• P271: Use only outdoors or in a well-ventilated area.
• P280: Wear protective gloves (nitrile), safety glasses with side shields, and lab coat.
• P301+P310: IF SWALLOWED: Immediately call a POISON CENTER or physician.
• P302+P352: IF ON SKIN: Wash with plenty of soap and water.
• P304+P340: IF INHALED: Remove person to fresh air and keep comfortable for breathing.
• P305+P351+P338: IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses if present and easy to do. Continue rinsing.
• P308+P313: IF exposed: Get medical advice/attention.
• P330: Rinse mouth if swallowed.
• P403+P233: Store in a well-ventilated place. Keep container tightly closed.
• P501: Dispose of contents/container in accordance with local, regional, and national regulations.
• First Aid Measures:
• Inhalation: Remove to fresh air. If breathing difficult, administer oxygen and seek medical attention immediately.
• Skin Contact: Immediately wash with plenty of soap and water for at least 15 minutes. Remove contaminated clothing. Seek medical advice if irritation or rash develops.
• Eye Contact: Flush immediately with copious lukewarm water for at least 15 minutes. Remove contact lenses if possible. Seek medical attention immediately.
• Ingestion: Rinse mouth. Do NOT induce vomiting. Give water to drink if conscious. Call a POISON CENTER immediately.
• Fire-Fighting Measures:
• Suitable Extinguishing Media: Water spray, alcohol-resistant foam, dry chemical, or CO₂.
• Special Hazards: Combustion may produce highly toxic fumes including HF (hydrogen fluoride), HCl (hydrogen chloride), chlorine gas (Cl₂), and nitrogen oxides (NOₓ).
• Protective Equipment: Wear self-contained breathing apparatus (SCBA) and full protective clothing.
• Spill Response:
• Avoid dust generation. Sweep up and place in a suitable closed container for disposal. Do NOT use combustible materials for cleanup. Do not allow entry to drains or waterways. Ventilate area after cleanup.
• Handling & Storage:
• Handle in fume hood ONLY. Keep container closed when not in use. Store at -20°C, protected from light and moisture. Keep away from strong oxidizers, strong acids/bases, and heat sources.
• Hazardous Decomposition Products: Hydrogen fluoride (HF), hydrogen chloride (HCl), chlorine gas (Cl₂), nitrogen oxides (NOₓ), carbon monoxide (CO).
• Intended Use: For laboratory research and development ONLY. Not for human or veterinary therapeutic, diagnostic, or food use. Handle as a potentially bioactive and cytotoxic compound.
