Bumped-Kinase Inhibitors as Castrate-Resistant Prostate Cancer Drugs
Abstract
Kinase inhibitors present exciting therapies for cancer including prostate cancer. We have developed a class of kinase inhibitors, bumped kinase inhibitors (BKIs), that have narrow kinase specificity due to their unique binding of the ATP-binding site and activity against androgen receptor (AR) positive prostate cancer cells. Despite of the life extending therapies of the newest drugs targeting the AR e.g. abiraterone and enzalutamide, tumors almost universally acquire resistance, and survival is extended by only four months. Hypotheses 1: BKIs are specific candidates for treatment of AR-driven CRPC. 2: BKIs act directly or indirectly by inhibition of ARSer81 phosphorylation necessary to activate AR to stimulate transcription. Study Design: In aim1, we will use BKI-kinome screening of prostate cancer cells to discover kinase targets of our BKIs, BKI induced changes in phosphoproteome, and BKI effects on pSer81 to determine the targets and pathways effected by BKIs. We currently have a good lead BKIs with EC50s of 8uM. However, a more ideal candidate to take to the clinic will have an EC50 of<3uM. A structureactivity relationship model (SAR) has been developed. Therefore, in Aim 2 additional BKIs will be synthesized using this SAR and screened for CRPC activity with a goal for an EC50 of < 3 M. Selected BKIs will be screened against enzalutamide resistant PDX models. A Target Candidate Profile (TCP) and work flow to evaluate BKIs for efficacy, pharmacokinetic and safety properties will efficiently direct us to choose a pre-clinical candidate for an IND
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2019
- Accession Number
- AD1095239
Entities
People
- Wesley I. Voorhis
Organizations
- University of Washington