Efficient identification of novel leads by dynamic focused screening: PDK1 case stud

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Drug Discovery

Background:

• Protein kinase PDK1 is a key target in various diseases.
• Traditional screening methods often yield limited novelty in identified inhibitors.
• Efficient identification of novel PDK1 inhibitors is crucial for therapeutic development.

Purpose of the Study:

• To explore a dynamic, focused screening strategy for identifying novel PDK1 inhibitors.
• To assess the efficiency and novelty of an iterative focused screening (IFS) approach.
• To compare the IFS approach with ultra-high throughput screening (uHTS) for lead identification.

Main Methods:

• Screening of approximately 21,500 compounds, including a 19,000-molecule kinase-focused compound collection (KFCC).
• Utilizing a machine-learning technique to build a predictive model for iterative focused screening (IFS).
• Employing a customized iterative focused screening (IFS) campaign with progressive removal of non-novel compounds.

Main Results:

• Identification of PDK1 inhibitors with unique chemotypes distinct from known compounds after three IFS rounds.
• The IFS approach successfully generated novel scaffolds for medicinal chemistry efforts.
• Retrospective analysis indicated IFS as a successful method for discovering novel scaffolds, complementary to uHTS.

Conclusions:

• The dynamic, focused screening strategy is an efficient method for identifying novel PDK1 inhibitors.
• Iterative focused screening (IFS) can overcome the novelty limitations of initial broad screens.
• This approach offers a complementary or alternative strategy to uHTS for rapid and efficient lead identification.