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Duocarmycin SA - CAS 130288-24-3 Catalog number: BADC-00813
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Duocarmycin SA is a potent antitumor antibiotic with an IC50 of 10 pM. Duocarmycin SA is an extremely potent cytotoxic agent capable of inducing a sequence-selective alkylation of duplex DNA. Duocarmycin SA demonstrates synergistic cytotoxicity against glioblastoma multiforme (GBM) cells treated with proton radiation in vitro.
Category
ADCs Cytotoxin
Product Name
Duocarmycin SA
CAS
130288-24-3
Catalog Number
BADC-00813
Molecular Formula
C25H23N3O7
Molecular Weight
477.47
Target
Ordering Information
| Catalog Number | Size | Price | Quantity |
|---|---|---|---|
| BADC-00813 | -- | $-- |
Description
Duocarmycin SA is a potent antitumor antibiotic with an IC50 of 10 pM. Duocarmycin SA is an extremely potent cytotoxic agent capable of inducing a sequence-selective alkylation of duplex DNA. Duocarmycin SA demonstrates synergistic cytotoxicity against glioblastoma multiforme (GBM) cells treated with proton radiation in vitro.
Synonyms
(+)-duocarmycin SA; Antibiotic DC113; methyl (1R,12S)-7-oxo-10-(5,6,7-trimethoxy-1H-indole-2-carbonyl)-5,10-diazatetracyclo[7.4.0.01,12.02,6]trideca-2(6),3,8-triene-4-carboxylate
IUPAC Name
methyl (1R,12S)-7-oxo-10-(5,6,7-trimethoxy-1H-indole-2-carbonyl)-5,10-diazatetracyclo[7.4.0.01,12.02,6]trideca-2(6),3,8-triene-4-carboxylate
Canonical SMILES
COC1=C(C(=C2C(=C1)C=C(N2)C(=O)N3CC4CC45C3=CC(=O)C6=C5C=C(N6)C(=O)OC)OC)OC
InChI
InChI=1S/C25H23N3O7/c1-32-17-6-11-5-14(26-19(11)22(34-3)21(17)33-2)23(30)28-10-12-9-25(12)13-7-15(24(31)35-4)27-20(13)16(29)8-18(25)28/h5-8,12,26-27H,9-10H2,1-4H3/t12-,25-/m1/s1
InChIKey
VQNATVDKACXKTF-XELLLNAOSA-N
Density
1.53±0.1 g/cm3 (Predicted)
Solubility
10 mm in DMSO
Melting Point
137-148 °C
LogP
2.74020
PSA
122.95000
Vapor Pressure
8.82E-25mmHg at 25°C
In Vitro
Although still exceptionally potent, the iso-duocarmycin SA derivatives and natural product analogues exhibited a corresponding approximate 3-5-fold reduction in cytotoxic activity [L1210 IC(50) for (+)-iso-duocarmycin SA = 50 pM and for (+)-iso-yatakemycin = 15 pM] consistent with their placement on a parabolic relationship correlating activity with reactivity. The DNA alkylation selectivity of the resulting key natural product analogues was unaltered by the structure modification in spite of the minor-groove presentation of a potential H-bond donor.
In Vivo
Duocarmycin SA (DSA) concentrations as low as 0.001 nM significantly sensitized U-138 cells to proton irradiation. DSA demonstrates synergistic cytotoxicity against GBM cells treated with proton radiation in vitro, which may represent a novel therapeutic alternative for the treatment of GBM.
Appearance
Pale Yellow Powder
Purity
98.0%
Shelf Life
0-4℃ for short term (days to weeks), or -20℃ for long term (months).
Shipping
Room temperature, or blue ice upon request.
Storage
-20°C
Boiling Point
787.7±60.0 °C (Predicted)
1. Duocarmycin SA, a potent antitumor antibiotic, sensitizes glioblastoma cells to proton radiation
Kristopher E Boyle, Dale L Boger, Andrew Wroe, Marcelo Vazquez Bioorg Med Chem Lett. 2018 Sep 1;28(16):2688-2692. doi: 10.1016/j.bmcl.2018.04.008. Epub 2018 Apr 4.
New treatment modalities for glioblastoma multiforme (GBM) are urgently needed. Proton therapy is considered one of the most effective forms of radiation therapy for GBM. DNA alkylating agents such as temozolomide (TMZ) are known to increase the radiosensitivity of GBM to photon radiation. TMZ is a fairly impotent agent, while duocarmycin SA (DSA) is an extremely potent cytotoxic agent capable of inducing a sequence-selective alkylation of duplex DNA. Here, the effects of sub-nM concentrations of DSA on the radiosensitivity of a human GBM cell line (U-138) to proton irradiation were examined. Radiation sensitivity was determined by viability, apoptosis, necrosis and clonogenic assays. DSA concentrations as low as 0.001 nM significantly sensitized U-138 cells to proton irradiation. DSA demonstrates synergistic cytotoxicity against GBM cells treated with proton radiation in vitro, which may represent a novel therapeutic alternative for the treatment of GBM.
2. Antibody-drug Conjugate PCMC1D3-Duocarmycin SA as a Novel Therapeutic Entity for Targeted Treatment of Cancers Aberrantly Expressing MET Receptor Tyrosine Kinase
Rachel Hudson, Hang-Ping Yao, Sreedhar Reddy Suthe, Dhavalkumar Patel, Ming-Hai Wang Curr Cancer Drug Targets. 2022;22(4):312-327. doi: 10.2174/1568009621666211222154129.
Background: Aberrant expression of the MET receptor tyrosine kinase is an oncogenic determinant and a drug target for cancer therapy. Currently, antibody-based biotherapeutics targeting MET are under clinical trials. Objective: Here, we report the preclinical and therapeutic evaluation of a novel anti-MET antibody- drug conjugate PCMC1D3-duocarmycin SA (PCMC1D3-DCM) for targeted cancer therapy. Methods: The monoclonal antibody PCMC1D3 (IgG1a/κ), generated by a hybridoma technique and specific to one of the MET extracellular domains, was selected based on its high specificity to human MET with a binding affinity of 1.60 nM. PCMC1D3 was conjugated to DCM via a cleavable valine-citrulline dipeptide linker to form an antibody-drug conjugate with a drug-to-antibody ratio of 3.6:1. PCMC1D3-DCM in vitro rapidly induced MET internalization with an internalization efficacy ranging from 6.5 to 17.2h dependent on individual cell lines. Results: Studies using different types of cancer cell lines showed that PCMC1D3-DCM disrupted the cell cycle, reduced cell viability, and caused massive cell death within 96h after treatment initiation. The calculated IC50 values for cell viability reduction were 1.5 to 15.3 nM. Results from mouse xenograft tumor models demonstrated that PCMC1D3-DCM in a single dose injection at 10 mg/kg body weight effectively delayed xenograft tumor growth up to two weeks without signs of tumor regrowth. The calculated tumoristatic concentration, a minimal dose required to balance tumor growth and inhibition, was around 2 mg/kg body weight. Taken together, PCMC1D3-DCM was effective in targeting the inhibition of tumor growth in xenograft models. Conclusion: This work provides the basis for the development of humanized PCMC1D3-DCM for MET-targeted cancer therapy in the future.
3. Glypican-3-Specific Antibody Drug Conjugates Targeting Hepatocellular Carcinoma
Ying Fu, Daniel J Urban, Roger R Nani, Yi-Fan Zhang, Nan Li, Haiying Fu, Hamzah Shah, Alexander P Gorka, Rajarshi Guha, Lu Chen, Matthew D Hall, Martin J Schnermann, Mitchell Ho Hepatology. 2019 Aug;70(2):563-576. doi: 10.1002/hep.30326. Epub 2019 Feb 19.
Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death in the world. Therapeutic outcomes of HCC remain unsatisfactory, and novel treatments are urgently needed. GPC3 (glypican-3) is an emerging target for HCC, given the findings that 1) GPC3 is highly expressed in more than 70% of HCC; (2) elevated GPC3 expression is linked with poor HCC prognosis; and (3) GPC3-specific therapeutics, including immunotoxin, bispecific antibody and chimeric antigen receptor T cells. have shown promising results. Here, we postulate that GPC3 is a potential target of antibody-drug conjugates (ADCs) for treating liver cancer. To determine the payload for ADCs against liver cancer, we screened three large drug libraries (> 9,000 compounds) against HCC cell lines and found that the most potent drugs are DNA-damaging agents. Duocarmycin SA and pyrrolobenzodiazepine dimer were chosen as the payloads to construct two GPC3-specific ADCs: hYP7-DC and hYP7-PC. Both ADCs showed potency at picomolar concentrations against a panel of GPC3-positive cancer cell lines, but not GPC3 negative cell lines. To improve potency, we investigated the synergetic effect of hYP7-DC with approved drugs. Gemcitabine showed a synergetic effect with hYP7-DC in vitro and in vivo. Furthermore, single treatment of hYP7-PC induced tumor regression in multiple mouse models. Conclusion: We provide an example of an ADC targeting GPC3, suggesting a strategy for liver cancer therapy.
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