KITCL27
KITCL27
In patients affected by idiopathic pulmonary fibrosis, alterations in PI3K signalling contribute to excessive fibroblast growth, which may limit pulmonary compliance and function. KITCL27 has been designed as a small molecule PI3K inhibitor that can block the enzymatic function of all members of the PI3K family. KITCL27 potentially offers a superior safety profile through its activity as a prodrug suitable for inhalation and activated only inside the target cells.
Contrary to the prodrug, the active compound is not cell-permeable hence it cannot leak to neighbouring cells but instead is rapidly eliminated from the blood and excreted with urine. As such, local administration ensures restricted activity to the target cells within lungs (Campa et al., Nature Communications 2018).
This pharmacological profile allows it to restrict the anti-PI3K activity to the first targeted cells following inhalation, thus drastically reducing the known toxic effects of PI3K inhibition. For example, systemic PI3K inhibitors alter the patient’s blood glucose levels, but KITCL27, when administered in the lungs, actively blocks the proliferation of IPF fibroblasts but has no global effect on blood glucose. On the other hand, pulmonary administration of KITCL27 showed significant anti fibrotic properties eventually reducing mortality in a mouse model of bleomycin-induced lung fibrosis (Campa et al., “Nature Communications” 2018).
Idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF) is a rare lung disease that, results in scarring (fibrosis) of the lungs. Over time, this scar formation worsens, making it hard for patients to take deep breaths. IPF is an interstitial lung disease, primarily involving the interstitium (the tissue and space around the air sacs of the lungs), and not directly affecting the airways or blood vessels. Scarring of the airways in response to COVID-19 infection shares some features with IPF and 30 to 50% of patients recovering from COVID-19 show pulmonary fibrotic remodelling. Currently, there are no drugs that can revert IPF and COVID-associated fibrotic remodelling of the lungs, but available treatments slow this degenerative process.
This pharmacological profile allows it to restrict the anti-PI3K activity to the first targeted cells following inhalation, thus drastically reducing the known toxic effects of PI3K inhibition. For example, systemic PI3K inhibitors alter the patient’s blood glucose levels, but KITCL27, when administered in the lungs, actively blocks the proliferation of IPF fibroblasts but has no global effects on blood glucose. On the other hand, pulmonary administration of KITCL27 showed significant anti fibrotic properties eventually reducing mortality in a mouse model of bleomycin-induced lung fibrosis (Campa et al., Nature Communications 2018).
PIPELINE
Lead candidates
Indication
Mode of therapy
Preclinical studies
clinical trial
Orphan Drug Designation
