Kither biotech is focused on the treatment of rare pulmonary diseases like Cystic Fibrosis (CF) and Idiopathic Pulmonary Fibrosis (IPF), two very different conditions for which little pharmacological treatments are currently available.
Kither developed two proprietary chemical moieties that act modulating signal transduction events controlled by PI3K enzymes.
As kinases, PI3K enzymes amplify extracellular signals inside the cell and control metabolism and proliferation. With these premises, Kither developed a small molecule inhibitor (KIT2012, also cited as CL27) with the ability of blocking the enzymatic function of all members of the PI3K family. KIT2012 was optimized for inhaled treatment with superior safety profile as a prodrug per se inactive but able to penetrate cell membranes as well as to be converted into the active compound inside cells. The active compound is negatively charged, non-diffusible and rapidly secreted by kidneys when in the blood (Campa et al., Nature Communications 2018). This pharmacological profile allows to restrict anti PI3K activity within the first targeted cells, so drastically reducing the known toxic effects of PI3K inhibition. For example, whereas systemic PI3K inhibitors alter glycaemia, KIT2012 administered in lungs actively blocks proliferation of IPF fibroblasts (Campa et al, Nature Communications 2018) but has no global effect on blood glucose. IPF is a disease where alterations in PI3K signaling contribute to excessive fibroblast growth that eventually limit pulmonary compliance and function. The ability of KIT2012 to act locally with limited side and systemic effects make it the ideal molecule for inhaled therapy of this serious condition, as observed in our preclinical studies (Campa et al., Nature Communications 2018).
On the other hand, the Kither team discovered in the past that PI3Ks are not only enzymes but also essential partners for other proteins. Past observations indicated that PI3Kgamma has two functions: on one hand it works as an enzyme but on the other as the aggregator of a series of partners controlling the cAMP signaling axis. Therefore, PI3Kgamma integrates two different signal transduction pathways: the classical PI3K pathway and the cAMP pathway (Perino et al., Molecular Cell 2011). In agreement with these findings, PI3Kgamma binds another kinase called PKA and restricts its function via a negative feedback loop involving type 3 and 4 phosphodiesterases (PDE3/4)
Preclinical observations in support show that the loss of the scaffold function of PI3Kgamma lead to decreased PDE3/4 activity and subsequent increased cAMP, which in lungs is paralleled by bronchodilation and anti-inflammatory effects. This led to the discovery of KIT2014, a cell-permeable peptide containing the PI3Kgamma sequence allowing the association with PKA. Inhaled KIT2014 increases cAMP and, leads to the phosphorylation and opening of the chloride channel CFTR. In cells and organoids of CF patients where mutations in CFTR cause reduced chloride, the treatment with KIT2014 helps restoring the function to an unprecedented level. Therefore, KIT2014 shares three useful pharmacological properties: it works as a bronchodilator as an anti-inflammatory agent and as a CFTR opener.
The intellectual property assets of the company comprise the following patents: