Optimisation of abiraterone based non-steroidal lead molecules

Abstract

Management of castration resistant prostate cancer is limited by androgen receptor reactivation resulting in loss of remission. A recent study indicated that abiraterone exhibits antagonist activity towards the androgen receptor in addition to CYP17A1 inhibition.Metribolone has demonstrable in vitro and in vivo high affinity for the AR thus it was established as a benchmark against which the affinity of abiraterone and de novo designed non-steroidal molecules could be compared. Binding affinities of abiraterone manually superimposed onto the steroid scaffold of metribolone (pKd 7.16) and abiraterone that was allowed limited rotation (pKd 7.23)were comparable to metribolone (pKd 7.44).The de novo study generated an 8 analogue molecular series with affinities ranging between 5.26 and 7.23. This study yielded sufficient analogues that may be proposed for further molecular optimisation to yield innovative non-steroidal high affinity molecules with superior side-effect profiles for the management of prostate cancer.