Thorsten Nowak
C4X Discovery
UK
Title: Ligand conformational analysis enabling improved Nrf2 activators
Biography
Biography: Thorsten Nowak
Abstract
Chronic Obstructive Pulmonary Disease (COPD) is an area of substantial unmet medical need. In particular, effective anti-inflammatory therapy is required in addition to bronchodilator therapy as disease severity progresses. While oral PDE4 inhibitors are currently used for this purpose and have been shown to be effective on exacerbation rates, their degree of efficacy is disappointing. In this regard, Nrf-2 activators have the potential to be efficacious on exacerbation rate with much a better tolerability profile. However, it has been difficult to create highly potent drug-like non-covalent inhibitors for the key Nrf2/Keap-1 protein-protein interaction (PPI).
Nrf2 is a master regulator of the cell’s antioxidant response and its activation leads to a coordinated antioxidant and anti-inflammatory response. Here we present a detailed 3D-structural analysis of a publicly available Nrf2 activator [1], which functions by blocking the interaction of Nrf2 with its repressor Keap-1.
The variety of conformations that the free activator adopts in solution was precisely measured using the NMR methodology of Blundell et al [2] and this data was combined with results from protein X-ray co-crystallography and in silico docking. The synergistic combination of these techniques provides unique insights into the disruption of this protein-protein interface, and demonstrates the power of combining ligand-based and structure-based drug design approaches. These data provide clear, immediate and rational strategies for both conventional and conformational design of the ligand to achieve improved potency.