Zytiga works by inhibiting the enzyme CYP17 which blocks androgen production in the body. Here is a picture of Zytiga binding into the active site of CYP17. There is a very precise moloecular fit of Zytiga into the CYP17 enzyme which explains why it is so potent at inhibiting this enzyme.
I'm pleased to see the technical trend with this comment. There should be a reference for the figure.
ReplyDeleteIt always seemed clear to me that abiraterone is a sterol analog that inhibits by binding into the sterol site and blocking it. But, then one would predict that it is a competitive inhibitor, not non-competitive as claimed by J&J.
On a related topic, what is the role of the acetate. (Zytiga is abiraterone acetate.) Acetate should make the drug more hydrophobic. It this part of the explanation for greater absorption of the drug when taken with a high fat meal? When is the acetate removed? In the gut? In the blood? Or, inside the tumor cells?
Yes, a great picture isn't it showing how well Abiraterone fits into the CYP17 active site. You're quite right, you would expect this type of haeme binding inhibitor to be reversible, but the fit is so precise that Zytiga becomes irreversibly bound to the active site. This locked into position by rotation of the pyridine ring by 80 degrees so that it points directly at the central iron atom of the haeme group forming a strong dative bond. This twisting of the pyridyl ring is thought to act like a toggle locking Abiraterone into the active site in addition to the haeme binding. This means that you only need a single molecule of Abiraterone to inhibit the CYP17 enzyme. So J&J are right and Zytiga is an irreversible inhibitor of CYP17.
ReplyDeleteThis is why Zytiga is superior to ther CYP17 inhibitors such as Ketoconazole and Oteronel (TAK-700) which are reversible inhibitors. Abiraterone Acetate (Zytiga) does not itself bind to the CYP17 enzyme and has to be cleaved to Abiraterone which is the active CYP17 inhibitor. The cleavage of Abiraterone Acetate to Abiraterone is carried out by plasma esterases in the bloodstream ready for delivery to the target organs. Abiraterone itself is not a very soluble compound having internal hydrogen bonds which make it poorly bioavailable. So Abiraterone was formulated as the Acetate ester derivative which has excellent bioavailability especially when taken with food where the solubility is increased with a high fat meal which induces bile secretion that aids uptake of the drug.