Potential strategies for increasing drug-discovery productivity

Area of Science:

• Drug discovery and development
• Pharmaceutical sciences
• Medicinal chemistry

Background:

• The pharmaceutical industry faces significant productivity challenges.
• Current strategies often focus on efficiency (e.g., Lean Six Sigma, modeling/simulation) rather than effectiveness.
• High clinical failure rates indicate a need for improved drug development approaches.

Purpose of the Study:

• To advocate for a paradigm shift in drug discovery, focusing on enhancing effectiveness.
• To propose redesigning the screening cascade for improved identification and optimization of drug candidates.
• To highlight the importance of disease-relevant efficacy over mere target potency.

Main Methods:

• Recommending the integration of disease-relevant phenotypic screens with traditional target-based assays.
• Advocating for an opportunistic approach to polypharmacology.
• Emphasizing optimization of the molecular mechanism of action.

Main Results:

• The proposed approach aims to reduce clinical failure rates by focusing on true therapeutic benefit.
• Integrating phenotypic screening drives medicinal chemistry optimization towards more effective compounds.
• Considering binding kinetics, covalent strategies, and allosteric modulation enhances drug optimization.

Conclusions:

• Redesigning the screening cascade is crucial for improving pharmaceutical industry productivity.
• Prioritizing disease efficacy and employing advanced optimization strategies can lead to more successful drug development.
• A holistic approach to drug design, encompassing mechanism, kinetics, and pharmacology, is essential.