Research Projects

Chronic obstructive pulmonary disease (COPD) is a chronic progressive lung disease leading to early death. It is one of the leading causes of morbidity and mortality worldwide due to high disease prevalence and the lack of effective therapies to address underlying inflammation. Even steroids show inadequate efficacy. Our objective is to develop a safe and efficacious Rho-associated coiled-coil kinase 2 (ROCK2) inhibitor as a novel therapy COPD, with the unique potential to slow disease progression. COPD involves chronic lung inflammation, characterized by inflammatory cell infiltration and release of multiple inflammatory mediators suggesting an essential role in its pathophysiology and the disease progression. ROCK1 and ROCK2, play an essential role in maintaining airways tone and in lung inflammation and remodeling, signifying that ROCK inhibitors may have a novel and critical role in COPD. A few non-selective ROCK inhibitors like Fasudil or Ripasudil are on the market. However, ROCK1 inhibition is associated with severe dose-limiting hypotension as an adverse effect. Therefore, there is a preference for ROCK2 isoform inhibitors devoid of the hypotensive side effect of systemic therapies. Also, ROCK2 is essential for smooth muscle contractions and the inflammatory effect. Earlier, Ezzie et al., (2012) reported selective upregulation of ROCK2 isoform in COPD patients but not ROCK1. ROCK inhibitors are also said to block TGF- induced airway remodeling and can cause fibrosis and defective lung repair associated with COPD disease progression. Another important aspect of COPD is TH2 and TH17, signature phenotypes, and in both cases, ROCK2 is over-expressed. It is critical as the IL-17A response signature is associated with the steroid-unresponsive COPD patient subgroup. Selective ROCK2 inhibition restores immune homeostasis and shifts the Th17/regulatory T cells (Tregs) balance toward Tregs, which provides a substantial role for selective ROCK2 inhibition in COPD. In this project, we already synthesized over 400 compounds targeting ROCK2 enzyme inhibition. We have identified five novel patentable scaffolds for lead optimization with some compounds showing low nM potency. We also propose to introduce emerging new technology - PROteolysis TArgeting Chimeras (PROTACs) which causes targeting protein degradation, unlike the conventional enzyme inhibitors. This approach offers a complete ablation of the target protein (ROCK2), providing an improved efficacy, safety, and better clinical outcome. This will be the first of its kind approach to target COPD. This also serves to differentiate from the competition. In this project, we propose to develop a selective ROCK2 degrader to demonstrate proof of concept in COPD using a degrader instead of an inhibitor. This will be a unique profile to offer novel therapeutic potential in COPD and has the potential to fulfill the unmet medical need associated with COPD considerably.