Development and Characterization of a Pan-PI3K Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis and Other PI3K-Driven Diseases

Idiopathic Pulmonary Fibrosis (IPF) is a progressive interstitial lung disease characterized by excessive extracellular matrix deposition, aberrant fibroblast proliferation, and irreversible loss of lung function. Despite the availability of antifibrotic agents such as Pirfenidone and Nintedanib, current therapies merely slow disease progression and are often discontinued due to dose-limiting toxicities. Aberrant activation of the phosphoinositide 3-kinase (PI3K)/Akt signalling pathway is increasingly recognized as a key driver of fibrotic remodelling, supporting the therapeutic potential of PI3K inhibition in IPF. Building upon the previously identified pan-PI3K inhibitor prodrug KITCL27, seven new analogues were rationally designed to optimize physicochemical and pharmacokinetic properties while retaining potent pathway inhibition. The main objective of this lead-optimization process was to design compounds that could effectively avoid both premature activation and delayed degradation, ensuring controlled release of the active drug at the target site. Six analogues were successfully synthesized, of which three demonstrated a threefold improvement in PI3K inhibitory potency compared with KITCL27 and produced clear dose-dependent cytostatic effects in mouse fibroblasts. These lead compounds exhibited low aqueous solubility, consistent with their lipophilic nature, but displayed acceptable metabolic stability in lung S9 fractions, suggesting efficient pulmonary activation. KITCL27 development was discontinued due to its excessive stability in human plasma (t1/2>120 min), which raised concerns of prolonged systemic exposure. In contrast, two of the three lead candidates demonstrated rapid conversion in human plasma. A (t1/2 = 4.8 min) and C (t1/2 = 12.9 min) showed approximately 25 fold and 10 fold faster degradation over KITCL27, respectively, marking a striking improvement in stability profiles. Thus, among this series, A or KITA emerged as the lead candidate, combining enhanced potency, appropriate physicochemical properties, and a favourable safety–efficacy profile. KITA has now been investigated in additional IPF models to reinforce its translational potential in IPF, as well as in therapeutic applications beyond IPF, namely other PI3K driven disorders like PIK3CA-related overgrowth syndromes (PROS). Collectively, these findings position KITA as a promising next-generation pan-PI3K inhibitor prodrug currently advancing through preclinical development for IPF and other PI3K-driven diseases