Thursday, April 17, 2025
4/17/2025
Role of Cdk9 in the Pathogenesis of Pulmonary Fibrosis - Project Summary/Abstract: The long-term objectives of this proposal are to reveal new and novel druggable targets and/or elements of fibrogenic pathways, thereby yielding new insights into better treatment strategies for idiopathic pulmonary fibrosis (IPF). IPF is one of the most frequent interstitial lung diseases and has a poor prognosis with worse outcomes than many malignant cancers. The two FDA-approved therapeutic agents (nintedanib and pirfenidone) have entered clinical use recently. Of most concern, while these drugs may slow the decline in lung function to a certain extent, both drugs fail to effectively halt lung fibrosis and improve patient survival. Therefore, there is an urgent need for new and improved therapeutics. In order to achieve higher clinical efficacy, current therapeutic approaches seek drugs that have dual activities against inflammation and fibrosis. To achieve dual activities effectively, we identified a novel central regulator, cyclin- dependent kinase 9 (Cdk9), that controls a common checkpoint for transcriptional activation of genes involved in major inflammatory and fibrotic signaling pathways. Preliminary data show that Cdk9 is elevated in IPF fibroblasts, which drives the aggressive nature of these cells. Treatment with Cdk9 inhibitor reduced the aggressiveness of the cells, and in mouse models of IPF, Cdk9 inhibitor increased survival and reduced fibrosis. These data support the hypothesis that Cdk9 inhibitors can be effective therapeutics to halt or reverse the progression of pulmonary fibrosis. This proposal aims to investigate the mechanistic roles of Cdk9 in IPF and validate Cdk9 as a new anti-inflammatory and anti-fibrotic pharmacotherapeutic target for treating IPF. The approach is to firmly establish a central role of Cdk9 in governing both inflammatory and fibrogenic processes. Our scientific premise rests upon the principle that a potent therapeutic approach to counteract inflammation and fibrosis concurrently can be attained by targeting Cdk9. Three specific aims are proposed, SA1) use gain-and-loss of function analyses to elucidate the molecular mechanism by which Cdk9 regulates IPF pathogenesis and progression, and screen a panel of clinical stage Cdk9 inhibitors for their effectiveness against fibrosis; SA2) test the therapeutic potential of the top performing Cdk9 inhibitor in a bleomycin-induced lung injury mouse model; and SA3) establish therapeutic proof-of-concept by developing an inhalable formulation of Cdk9 inhibitor and demonstrating efficacy in the bleomycin mouse model. Our vision is to generate pre-clinical mechanism-of-action data to support future development of a Cdk9 inhibitor-based IPF therapeutics.
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