Natural Product Bis-Intercalator Depsipeptides as a New Class of Payloads for Antibody-Drug Conjugates.
Anokha S RatnayakeLi-Ping ChangL Nathan TumeyFrank LoganzoJoseph A ChemlerMelissa WagenaarSylvia MustoFengping LiJeffrey E JansoT Eric BallardBrian RagoGreg L SteeleWeiDong DingXidong FengChristine HosseletVlad BuklanJudy LucasFrank E KoehnChristopher J O'DonnellEdmund I GrazianiPublished in: Bioconjugate chemistry (2018)
A potent class of DNA-damaging agents, natural product bis-intercalator depsipeptides (NPBIDs), was evaluated as ultrapotent payloads for use in antibody-drug conjugates (ADCs). Detailed investigation of potency (both in cells and via biophysical characterization of DNA binding), chemical tractability, and in vitro and in vivo stability of the compounds in this class eliminated a number of potential candidates, greatly reducing the complexity and resources required for conjugate preparation and evaluation. This effort yielded a potent, stable, and efficacious ADC, PF-06888667, consisting of the bis-intercalator, SW-163D, conjugated via an N-acetyl-lysine-valine-citrulline- p-aminobenzyl alcohol- N, N-dimethylethylenediamine (AcLysValCit-PABC-DMAE) linker to an engineered variant of the anti-Her2 mAb, trastuzumab, catalyzed by transglutaminase.
Keyphrases
- dna binding
- ionic liquid
- cancer therapy
- induced apoptosis
- transcription factor
- room temperature
- anti inflammatory
- cell cycle arrest
- circulating tumor
- single molecule
- risk assessment
- mass spectrometry
- magnetic resonance
- endoplasmic reticulum stress
- diffusion weighted
- molecularly imprinted
- monoclonal antibody
- climate change
- amino acid
- liquid chromatography
- crystal structure