526 A potent PBD-heterocyclic polyamide conjugate targeting an ICB2 transcription factor binding site

Brucoli, Federico; Hawkins, Rachel M.; Wells, Geoff; Jenkins, Terence C.; Ellis, Tom; Kotecha, Minal; Hochhauser, Daniel; Hartley, JA; Howard, Philip W.; Thurston, DE

doi:10.1016/s1359-6349(10)72233-3

Cited by 2 publications

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“…In this model, the C7-sibirosamine substituent of sibiromycin when docked at the 5′-AGT-3′ site directly interacted with Arg 46 of homodimer B (red surface, Figure ) which could prevent binding of the protein and explain the potent cytotoxicity observed for sibiromycin. There is growing interest in the use of PBD-type molecules as selective transcription factor inhibitors, ,− so this observation suggests that it may prove possible to increase the inhibitory activity of PBDs as a class by adding bulky substituents to the C7-position.…”

Section: Resultsmentioning

confidence: 99%

Computational Studies Support the Role of the C7-Sibirosamine Sugar of the Pyrrolobenzodiazepine (PBD) Sibiromycin in Transcription Factor Inhibition

et al. 2014

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The pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a group of sequence-selective, DNA minor-groove binding agents that covalently attach to guanine residues. Originally derived from Streptomyces species, a number of naturally occurring PBD monomers exist with varying A-Ring and C2-substituents. One such agent, sibiromycin, is unusual in having a glycosyl residue (sibirosamine) at its A-Ring C7-position. It is the most cytotoxic member of the naturally occurring PBD family and has the highest DNA-binding affinity. Recently, the analogue 9-deoxysibiromyin was produced biosynthetically by Yonemoto and co-workers.1 Differing only in the loss of the A-Ring C9-hydroxyl group, it was reported to have a significantly higher DNA-binding affinity than sibiromycin based on DNA thermal denaturation studies, although these data have since been retracted.2 As deletion of the C9-OH moiety, which points toward the DNA minor groove floor, might intuitively be expected to reduce DNA-binding affinity through the loss of hydrogen bonding, we carried out molecular dynamics simulations on the interaction of both molecules with DNA over a 10 ns time-course in explicit solvent. Our results suggest that the two molecules may differ in their sequence-selectivity and that 9-deoxysibiromycin should have a lower binding affinity for certain sequences of DNA compared to sibiromycin. Our molecular dynamics results indicate that the C7-sibirosamine sugar does not form hydrogen bonding interactions with groups in the DNA minor-groove wall as previously reported, but instead points orthogonally out from the minor groove where it may inhibit the approach of DNA control proteins such as transcription factors. This was confirmed through a docking study involving sibiromycin and the GAL4 transcription factor, and these results could explain the significantly enhanced cytotoxicity of sibiromycin compared to other PBD family members without bulky C7-substituents.

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Section: Resultsmentioning

confidence: 99%

Computational Studies Support the Role of the C7-Sibirosamine Sugar of the Pyrrolobenzodiazepine (PBD) Sibiromycin in Transcription Factor Inhibition

et al. 2014

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Pyridinobenzodiazepines (PDDs) as Sequence-selective DNA Mono-alkylating Antibody–Drug Conjugate (ADC) Payloads

Veillard

Cascio

Jackson

et al. 2019

Cytotoxic Payloads for Antibody – Drug Conjugates

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Although five ADCs have been approved and over sixty others are in development, the majority contain payloads belonging to two classes: tubulin inhibitors and DNA-interactive agents. Challenges in the development of ADCs include managing off-target toxicity and hydrophobicity. Some DNA-interactive payload classes [e.g. pyrolobenzodiazepine (PBD] dimers) are notably hydrophobic, leading to problems such as aggregation during conjugation, and systemic toxicities of the resultant ADCs are also beginning to emerge in clinical settings. Thus, there is interest in developing novel payloads which retain the potency of DNA cross-linking agents but have lower hydrophobicity and a wider therapeutic window when part of an ADC. The pyridinobenzodiazepines (PDDs) are a new class of sequence-selective, DNA mono-alkylating ADC payload, which contain a polyheterocyclic chain with sufficient molecular span and DNA base-pair recognition properties to guide them to specific DNA sequences (e.g. transcription factor binding sites). The favourable hydrophobicity profile of the PDDs and ease of conjugation, along with their novel mechanism of action, significant in vitro cytotoxicity and in vivo tolerability and efficacy when in an ADC format, indicate that they represent a promising new class of ADC payloads.

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526 A potent PBD-heterocyclic polyamide conjugate targeting an ICB2 transcription factor binding site

Cited by 2 publications

References 0 publications

Computational Studies Support the Role of the C7-Sibirosamine Sugar of the Pyrrolobenzodiazepine (PBD) Sibiromycin in Transcription Factor Inhibition

Computational Studies Support the Role of the C7-Sibirosamine Sugar of the Pyrrolobenzodiazepine (PBD) Sibiromycin in Transcription Factor Inhibition

Pyridinobenzodiazepines (PDDs) as Sequence-selective DNA Mono-alkylating Antibody–Drug Conjugate (ADC) Payloads

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