Pyrrolobenzodiazepine (PBD)

Structure of Pyrrolobenzodiazepine
Structure of Pyrrolobenzodiazepine

Pyrrolobenzodiazepine (PBD)
Chemical Name: [1,2]Diazepino[3,4-e]indole;
Molecular Formula: C14H14N2O3
Molecular weight 258,27 g/mole
Average mass: 181.193 Da
Monoisotopic mass: 181.063995 Da

Pyrrolobenzodiazepine (PBDs) are a class of sequence-selective DNA minor-groove binding crosslinking agents originally discovered in Streptomyces species. They are significantly more potent than systemic chemotherapeutic drugs.

Novel results demonstrate that PBDs can be effectively used for antibody-targeted therapy. [1] [2] [3]

Biological Activity
The mechanism of action of the PBDs is associated with their ability to form, an adduct in the minor groove, thus interfering with DNA processing. After insertion in the minor groove, an aminal bond is formed through nucleophilic attack of the N2 of a guanine base at the electrophillic C11 position of PBD.[4]

What are Pyrrolobenzodiazepines?
Pyrrolobenzodiazepines, a class of natural products produced by various actinomycetes (a broad group of bacteria that form thread-like filaments in the soil and are responsible for the distinctive scent of freshly exposed, moist soil), are sequence selective DNA alkylating compounds with significant antitumor properties. As a class of DNA-crosslinking agents they are significantly more potent than systemic chemotherapeutic drugs. Some PBDs have the ability to recognize and bond to specific sequences of DNA.[5][7]

PBD dimers bind in the minor groove of DNA, where they form covalent aminal cross- links between the N2 of guanine and the C11 position of the PBD. The resulting PBD-DNA adducts cause replication forks to stall and tumor cells to arrest at the G2-M boundary, ultimately resulting in ap- optosis at low nanomolar to picomolar concentrations. PBD dimers are particularly potent because of their cell cycle–independent activity and because their integration minimally distorts DNA, increas- ing the likelihood of evasion of DNA damage repair responses. Be- cause of the potency of PBD dimers and similar cell cycle–independent payloads, normal tissues accessed by such potently armed ADCs must be devoid of target expression.[6]

As DNA minor groove binding agents, pyrrolobenzodiazepines bind and cross-link specific sites of DNA of the cancer cell. This blocks the cancer cells’ division without distorting its DNA helix, thus potentially avoiding the common phenomenon of emergent drug resistance.

Anthramycin
The first pyrrolobenzodiazepines antitumour antibiotic, anthramycin (not to be confused with anthracimycin), produced by streptomyces refuineus, was discovered in 1965.

Since then, a number of naturally occurring PBDs have been reported, and over 10 synthetic routes have been developed to a variety of analogues. Other agents belonging to the pyrrolo(1,4)benzodiazepine antibiotic group include abbeymycin, chicamycin, DC-81, mazethramycin, neothramycins A and B , porothramycin prothracarcin, sibanomicin (DC-102) sibiromycin and tomamycin.[7]

Potency
In vitro, pyrrolobenzodiazepines typically demonstrate IC50 values in the low to mid picomolar range in a variety of cell types, and unlike the anti-tubulin agents, they can induce cell death in both dividing and non-dividing cells. Fully synthetic PBD dimers are ideally suited for the role of payload in an antibody-drug conjugate because, unlike other cytotoxic payloads such as calicheamycin, they combine potency with a demonstrated therapeutic index, are not cross-resistant with widely used chemotherapy agents, and their unique mode of action sets them apart from the tubulin binders such as maytansinoids and auristatins that currently dominate the antibody-drug conjugate arena.

The pyrrolobenzodiazepine (PBD) dimers are significantly more potent than systemic chemotherapeutic drugs and the site-specific conjugation technology allows uniform drug-loading of the cell-killing PBD agent to the anti-CD33 antibody. Pyrrolobenzodiazepine dimers have been shown to have broad spectrum anti-tumour activity in vivo. These novel drugs exert their activity by binding in the minor groove of DNA and linking the two DNA strands together in a way that cells find difficult to recognise and repair.

Development
Spirogen, a wholly-owned subsidiary of AstraZeneca’s MedImmune founded in 2001 as a spin-out from several institutions including University College London and with partial funding by Cancer Research UK, has developed a novel class of highly potent cytotoxic warheads based on its proprietary pyrrolobenzodiazepines (PBDs). The company has been developing its PBD technology for more than ten years, including a standalone PBD agent in a Phase II study in acute myeloid leukemia.

Pyrrolobenzodiazepine_DimerPyrrolobenzodiazepine Dimer
Molecular Formula: C31H32N4O6
Molecular Weight: 556,61 g/mole

 

See: ADC Review / Knowledge Center 

Clinical development with Pyrrolobenzodiazepine (PBD)

AbbVie/Stemcentrx

Seattle Genetics

ADC Therapeutics

  • ADCT-301
  • ADCT-402

Reference:
[1] Antonow D, Thurston DE (2011) Synthesis of DNA-interactive pyrrolo[2,1-c][1,4]benzodiazepines (PBDs). Chem Rev 111: 2815–2864. doi: 10.1021/cr100120f
[2] Cipolla L, Araujo AC, Airoldi C, Bini D (2009) Pyrrolo[2,1-c][1,4]benzodiazepine as a scaffold for the design and synthesis of anti-tumour drugs. Anticancer Agents Med Chem 9: 1–31. doi: 10.2174/187152009787047743
[3] Gerratana B (2012) Biosynthesis, synthesis, and biological activities of pyrrolobenzodiazepines. Med Res Rev 32: 254–293. doi: 10.1002/med.20212
[4] Li W, Khullar A, Chou S, Sacramo A, Gerratana B. Biosynthesis of sibiromycin, a potent antitumor antibiotic. Appl Environ Microbiol. 2009 May;75(9):2869-78. doi: 10.1128/AEM.02326-08. Epub 2009 Mar 6.
[5] Rahman KM, Jamesa CH, Thurston DE. Observation of the reversibility of a covalent pyrrolobenzodiazepine (PBD) DNA adduct by HPLC/MS and CD spectroscopy. Org. Biomol. Chem., 2011,9, 1632-1641. DOI: 10.1039/C0OB00762E
[6] Saunders LR, Bankovich AJ, Anderson WC, Aujay MA, Bheddah S, Black K, Desai R, et al. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med. 2015 Aug 26;7(302):302ra136. doi: 10.1126/scitranslmed.aac9459.
[7] Hu Y, Phelan V, Ntai I, Farnet CM, Zazopoulos E, Bachmann BO. Benzodiazepine biosynthesis in Streptomyces refuineus. Chem Biol. 2007 Jun;14(6):691-701.

Last Editorial Review: March 16, 2015