Target Validation, Lead Discovery, and Lead Optimization for Neglected Diseases

My group focuses on the discovery and preclinical development of new therapeutic leads for neglected diseases. We place a major focus on discovering new therapeutic chemotypes, determining their mechanism of action, and conducting proof-of-concept studies in pharmacokinetic/pharmacodynamic (PK/PD) models of disease. All of the projects are intended to deliver well-validated compounds that have suitable pharmacokinetic and toxicology profiles for detailed in vivo studies.  During my independent career, both historically and currently, the projects in my laboratory have been split roughly equally between oncology and protozoal diseases.

Our work spans the entire process from initial identification of new chemical hits through optimization of late leads in animal models and finally to the design and execution of human clinical trials. To date, our work has identified dozens of potential new leads for these diseases with novel mechanisms of action or novel applications.  We have contributed to repurposing drugs for clinical trials for ependymoma, infantile ALL, and medulloblastoma; contributed a repurposed clinical candidate for retinoblastoma; and produced a novel clinical candidate, (+)-SJ733, for the treatment of malaria that is currently entering Phase 2 trials (

General Methodology

Early Discovery

To find new chemical leads, we employ two primary approaches:

1) High-throughput screening in both biochemical and cellular models (Figure 1)

2) Target-based approaches, including design and fragment strategies

Figure 1. Scatter plot of primary screen data shown as normalized percent inhibition.  Each dot represents the activity of one compound and controls represent plate matched in plate controls (positive control (green); negative control (red), and test compounds (hits blue and non-hits black).

Hit Optimization

To identify and optimize the best early leads, we bring diverse disciplines together in a team that works through rounds of hypothesis-driven optimization to balance potency, efficacy, bioavailability, and toxicology (Figure 2), we:

1) Build testable hypothesis-based models from structure activity and structure property data to predict potency, selectivity, and bioavailability

2) Use parallel chemistry to accelerate hypothesis testing

3) Assay compounds for  cellular activities, bioche
mical activities, and cellular bioavailability and stability

Figure 2: The process of going from a new lead to an optimized lead is one of building knowledge and applying chemistry.

Late Lead Optimization

To optimize late leads for the best balance of properties (Figure 3) for use in animal models, we:

1) Take best leads forward into the “real world” of rodent models and use resulting data to identify their liabilities, such as toxicology or poor bioavailability, and improve their performance

2) Collaborate with disease-focused groups to assess efficacy and potency in state-of-the-art animal models

3) Balance bioavailability, toxicology, and effect to provide the best possible performance

Figure 3. The process of going from a new lead to an optimized lead is one of building knowledge and applying chemistry.

Current Research Projects