Targeting RNA Polymerase II
anti-RNA polymerase II ADC
Death of Socrates - Jacques-Louis David (1787)
"Death Cap " mushroom
Alpha-amanitin is derived from Amanita phalloides, the notorious "Death Cap" mushroom, which has been used for assassinations dating back to antiquity.
We are currently developing ADCs against CD125+ muscle invasive bladder cancer and HER2+ cancers that can escape endosome entrapment and route to the nucleus (via the technology Accum) and deliver alpha-amanitin effectively to RNA Polymerase II. Click on video to see how alpha-amanitin fits into the transcription pocket of RNA Polymerase II and blocks transcription.
DNA alkylator-armed ADC
The Death of Alexander the Great - Jean Restout (1730s)
In 2010, research presented tantalizing evidence that the toxic bacterium Micromonospora echinospora harbored by the ancient Styx River (modern day Egypt) might have been the reason for the poison rumored to have killed Alexander the Great (356-323 B.C.). According to the study, calicheamicin, a metabolite of Micromonospora echinospora is what gave the river its toxic reputation. Read report here.
Calicheamicin is a DNA alkylator that is too potent to administer in patients with out causing severe toxicity. Hence, it must be targeted.
This project is to develop Accum-modified ADCs that transport calicheamicin. We are also developing a similar alkylating cytotoxin duocarmycin.
Calicheamicin gamma 1 (aquamarine) binding in the minor groove of DNA where it preferentially binds to T-C-C-T (pink) - A-G-G-A (blue) regions.
ADC targeting the cell cycle
Targeted inhibition of CDK2
The protein CDK2, which is an important regulator for the cell cycle is aberrantly active in cancer. Here, CDK2 (teal) the protein becomes increasingly transparent revealing a novel small molecule inhibitor (magenta) in the binding pocket usually reserved for ATP. The yellow stick structures represent important amino acids in the binding pocket required for strong inhibition by this novel drug.