PBD dimer - CAS 1222490-34-7

PBD dimer - CAS 1222490-34-7 Catalog number: BADC-00340

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PBD dimer is a cytotoxic agent, used as the cytotoxic component in antibody-drug conjugates.

Category
ADCs Cytotoxin
Product Name
PBD dimer
CAS
1222490-34-7
Catalog Number
BADC-00340
Molecular Formula
C42H39N5O7
Molecular Weight
725.79
Target
DNA
PBD dimer

Ordering Information

Catalog Number Size Price Quantity
BADC-00340 1 mg $939
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Description
PBD dimer is a cytotoxic agent, used as the cytotoxic component in antibody-drug conjugates.
Synonyms
8-(3-((2-(4-Aminophenyl)-7-methoxy-5-oxo-1,11abeta-dihydro-5H-pyrrolo(2,1-C)(1,4)benzodiazepine-8-yl)oxy)propoxy)-7-methoxy-2-(4-methoxyphenyl)-1,11abeta-dihydro-5H-pyrrolo(2,1-C)(1,4)benzodiazepine-5-one;
IUPAC Name
(6aS)-3-[3-[[(6aS)-2-methoxy-8-(4-methoxyphenyl)-11-oxo-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]propoxy]-8-(4-aminophenyl)-2-methoxy-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-11-one
Canonical SMILES
COc1ccc(cc1)C2=CN3[C@@H](C2)C=Nc4cc(OCCCOc5cc6N=C[C@@H]7CC(=CN7C(=O)c6cc5OC)c8ccc(N)cc8)c(OC)cc4C3=O
InChI
InChI=1S/C42H39N5O7/c1-50-32-11-7-26(8-12-32)28-16-31-22-45-36-20-40(38(52-3)18-34(36)42(49)47(31)24-28)54-14-4-13-53-39-19-35-33(17-37(39)51-2)41(48)46-23-27(15-30(46)21-44-35)25-5-9-29(43)10-6-25/h5-12,17-24,30-31H,4,13-16,43H2,1-3H3/t30-,31-/m0/s1
InChIKey
OMRPLUKQNWNZAV-CONSDPRKSA-N
Density
1.4±0.1 g/cm3
Flash Point
545.1±34.3 °C
Index Of Refraction
1.676
LogP
2.87
Vapor Pressure
0.0±0.3 mmHg at 25°C
In Vitro
The PBD dimer binds only moderately to proteins (65-75%), and in vitro cytotoxicity studies confirmed IC(50) values of 4-30 nM with a panel of human cell lines.
In Vivo
Antibody-drug conjugates (ADC) containing pyrrolobenzodiazepine (PBD) dimers are being evaluated clinically in both hematologic and solid tumors. These include ADCT-301 (camidanlumab tesirine) and ADCT-402 (loncastuximab tesirine) in pivotal phase II trials that contain the payload tesirine, which releases the PBD dimer warhead SG3199. An important consideration in future clinical development is acquired resistance. The aim was to generate and characterize PBD acquired resistant cell lines in both hematologic and solid tumor settings. Human Karpas-299 (ALCL) and NCI-N87 (gastric cancer) cells were incubated with increasing IC50 doses of ADC (targeting CD25 and HER2, respectively) or SG3199 in a pulsed manner until stable acquired resistance was established. The level of resistance achieved was approximately 3,000-fold for ADCT-301 and 3-fold for SG3199 in Karpas-299, and 8-fold for ADCT-502 and 4-fold for SG3199 in NCI-N87. Cross-resistance between ADC and SG3199, and with an alternative PBD-containing ADC or PBD dimer was observed. The acquired resistant lines produced fewer DNA interstrand cross-links, indicating an upstream mechanism of resistance. Loss of antibody binding or internalization was not observed. A human drug transporter PCR Array revealed several genes upregulated in all the resistant cell lines, including ABCG2 and ABCC2, but not ABCB1(MDR1).
Appearance
Soild powder
Purity
≥95%
Shipping
Room temperature
Boiling Point
977.7±65.0 °C at 760 mmHg
1. Pre-clinical pharmacology and mechanism of action of SG3199, the pyrrolobenzodiazepine (PBD) dimer warhead component of antibody-drug conjugate (ADC) payload tesirine
David G Williams, Simon Chivers, John A Hartley, Arnaud Tiberghien, Michael J Flynn, Jay Harper, Francesca Zammarchi, Halla Reinert, John P Bingham, Luke A Masterson, Philip W Howard, Simon Corbett, Carin E G Havenith, Sajidah Chowdhury, Shenlan Mao, Dyeison Antonow, Patrick H van Berkel, Lauren Adams Sci Rep . 2018 Jul 11;8(1):10479. doi: 10.1038/s41598-018-28533-4.
Synthetic pyrrolobenzodiazepine (PBD) dimers, where two PBD monomers are linked through their aromatic A-ring phenolic C8-positions via a flexible propyldioxy tether, are highly efficient DNA minor groove cross-linking agents with potent cytotoxicity. PBD dimer SG3199 is the released warhead component of the antibody-drug conjugate (ADC) payload tesirine (SG3249), currently being evaluated in several ADC clinical trials. SG3199 was potently cytotoxic against a panel of human solid tumour and haematological cancer cell lines with a mean GI50of 151.5 pM. Cells defective in DNA repair protein ERCC1 or homologous recombination repair showed increased sensitivity to SG3199 and the drug was only moderately susceptible to multidrug resistance mechanisms. SG3199 was highly efficient at producing DNA interstrand cross-links in naked linear plasmid DNA and dose-dependent cross-linking was observed in cells. Cross-links formed rapidly in cells and persisted over 36 hours. Following intravenous (iv) administration to rats SG3199 showed a very rapid clearance with a half life as short as 8 minutes. These combined properties of cytotoxic potency, rapid formation and persistence of DNA interstrand cross-links and very short half-life contribute to the emerging success of SG3199 as a warhead in clinical stage ADCs.
2. From Anthramycin to Pyrrolobenzodiazepine (PBD)-Containing Antibody-Drug Conjugates (ADCs)
Khondaker M Rahman, David E Thurston, Paul J M Jackson, Julia Mantaj Angew Chem Int Ed Engl . 2017 Jan 9;56(2):462-488. doi: 10.1002/anie.201510610.
The pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a family of sequence-selective DNA minor-groove binding agents that form a covalent aminal bond between their C11-position and the C2-NH2groups of guanine bases. The first example of a PBD monomer, the natural product anthramycin, was discovered in the 1960s, and the best known PBD dimer, SJG-136 (also known as SG2000, NSC 694501 or BN2629), was synthesized in the 1990s and has recently completed Phase II clinical trials in patients with leukaemia and ovarian cancer. More recently, PBD dimer analogues are being attached to tumor-targeting antibodies to create antibody-drug conjugates (ADCs), a number of which are now in clinical trials, with many others in pre-clinical development. This Review maps the development from anthramycin to the first PBD dimers, and then to PBD-containing ADCs, and explores both structure-activity relationships (SARs) and the biology of PBDs, and the strategies for their use as payloads for ADCs.
3. ADCT-402, a PBD dimer-containing antibody drug conjugate targeting CD19-expressing malignancies
Peter C Tyrer, Simon Chivers, Konstantinos Kiakos, Teresa Marafioti, Charles E Britten, Francois D'Hooge, David G Williams, Arnaud Tiberghien, John A Hartley, Francesca Zammarchi, Philip W Howard, Simon Corbett, Narinder Janghra, Carin E G Havenith, Patrick H van Berkel, Lauren Adams Blood . 2018 Mar 8;131(10):1094-1105. doi: 10.1182/blood-2017-10-813493.
Human CD19 antigen is a 95-kDa type I membrane glycoprotein in the immunoglobulin superfamily whose expression is limited to the various stages of B-cell development and differentiation and is maintained in the majority of B-cell malignancies, including leukemias and non-Hodgkin lymphomas of B-cell origin. Coupled with its differential and favorable expression profile, CD19 has rapid internalization kinetics and is not shed into the circulation, making it an ideal target for the development of antibody-drug conjugates (ADCs) to treat B-cell malignancies. ADCT-402 (loncastuximab tesirine) is a novel CD19-targeted ADC delivering SG3199, a highly cytotoxic DNA minor groove interstrand crosslinking pyrrolobenzodiazepine (PDB) dimer warhead. It showed potent and highly targeted in vitro cytotoxicity in CD19-expressing human cell lines. ADCT-402 was specifically bound, internalized, and trafficked to lysosomes in CD19-expressing cells and, following release of the PBD warhead, resulted in formation of DNA crosslinks that persisted for 36 hours. Bystander killing of CD19-cells by ADCT-402 was also observed. In vivo, single doses of ADCT-402 resulted in highly potent, dose-dependent antitumor activity in several subcutaneous and disseminated human tumor models with marked superiority to comparator ADCs delivering tubulin inhibitors. Dose-dependent DNA crosslinks and γ-H2AX DNA damage response were measured in tumors by 24 hours after single dose administration, whereas matched peripheral blood mononuclear cells showed no evidence of DNA damage. Pharmacokinetic analysis in rat and cynomolgus monkey showed excellent stability and tolerability of ADCT-402 in vivo. Together, these impressive data were used to support the clinical testing of this novel ADC in patients with CD19-expressing B-cell malignancies.
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