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Targeting WWP2 for Treating Diseases Characterized by Fibrosis
Duke-NUS Medical School
Small molecule
Cardiovascular disease, Nephrology
Pre-Clinical
Unmet Needs and Current Approach
Tissue fibrosis occurs when the ongoing natural healing process in tissue is dysregulated, which as a consequence creates damaging extra scar tissue. Although substantial progress has been made in understanding the pathogenesis of excessive tissue fibrosis and fibrotic disorders, there is still no effective (and safe) cure. As fibrosis and resultant organ failure account for at least one-third of natural deaths worldwide, management of fibrotic diseases still present an important economic burden for human health. There are several common important fibrotic diseases (atherosclerosis, cirrhosis, scleroderma, pulmonary fibrosis, etc.) and since there are no effective treatments to prevent fibrotic tissue from forming, fibrosis is often considered to be an irreversible process. In the clinic, doctors typically try to slow down the fibrotic progress by anti-inflammatory and immunosuppressive drugs, which however lack specificity and present considerable toxicity. Thus, effective and adverse-side-effect free therapies for fibrotic diseases have not been achieved yet.
Our Solution
In an attempt to overcome these obstacles, scientists from the Cardiovascular and Metabolic Disorders Research Programme at Duke-NUS conducted an array of bioinformatics analyses to identify novel molecular candidates that are linked to fibrosis and found an E3 ubiquitin ligase called WWP2 to be pivotal in the pro-fibrosis molecular network. With the aid of in vitro loss- and gain-of-function studies, and WWP2 knockout mouse models, our scientists have shown that WWP2 is a key regulator of the extracellular matrix (ECM) accumulation in the diseased heart downstream of TGFβ/SMAD signalling. This pro-fibrotic function of WWP2 was found to be mainly associated with its N-terminal region, which our scientists believe is a novel and druggable therapeutic target with the potential to control fibrosis in pathological cardiac remodelling. In addition, WWP2 was also found to be a key factor augmenting kidney fibrosis. In summary, Duke-NUS scientists identified a novel, specific, well-validated drug target for treating tissue fibrosis.
Duke-NUS scientists are currently conducting pre-clinical testing of candidate small molecule compounds using in-house in vitro and in vivo models of heart and kidney fibrosis to identify lead compounds for clinical development.
Huimei Chen, Aida Moreno-Moral
PCT-EP2020-066260 (2020.06.12)
Patent Family: US, EP, CN
• "WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling". Huimei Chen et al. Nat Commun. 2019 Sep 9;10(1):4085
• "The E3 ubiquitin ligase WWP2 regulates profibrogenic monocyte infiltration and activity in heart fibrosis". Chen at al. Nature
Communications 2022
• "WWP2 mediates the metabolic reprogramming of renal myofibroblasts to promote kidney fibrosis". Chen et al. bioRxiv
2023.08.22.554242; doi: https://doi.org/10.1101/2023.08.22.554242
