View Abstract

A7772 - First-in-Class MAPK/PI3K Small Molecule Exhibits Reversal of Fibroproliferative Disease
Author Block: B. D. Ross1, S. Galban1, B. A. Hoff2, M. Van Dort1, C. Espinoza1, X. Xu3, W. D. Hardie4; 1Radiology, University of Michigan, Ann Arbor, MI, United States, 2Department of Radiology, University of Michigan, Ann Arbor, MI, United States, 3Pediatrics, University of Cincinnati Children’s Hospital, Cincinnati, OH, United States, 4Childrens Hosp Med Ctr, Cincinnati, OH, United States.
Idiopathic pulmonary fibrosis (IPF) contributes to morbidity and mortality in a range of diseases via the formation of pulmonary fibrotic lesions which progress to impair gas exchange and ultimately cause death. To date clinical trials have failed to advance a drug candidate which successfully reverses fibrotic progression. In murine IPF models, simultaneous inhibition of the mitogen activated protein kinase (MAPK) and phosphatidylinositide 3-kinases (PI3K) pathways has implicated both pathways in directly mediating fibroproliferative cellular processes including cell growth, proliferation and protection from apoptosis. Additionally, lung biopsies of patients with IPF demonstrate increased levels of signaling intermediates regulating the MAPK and PI3K pathways compared with normal lungs. As both pathways regulate overlapping cellular processes and demonstrate cross talk allowing for feedback activation of alternate pathways, inhibiting either MAPK-ERK or PI3K pathways alone is unlikely to be sufficient to alter aberrant downstream cellular processes and successful therapeutics will need to achieve inhibition of multiple pathways. However, clinical development of MEK/PI3K/mTOR combination therapies have been hampered by systemic toxicities in cancer clinical trials thus co-targeting of these pathways with combinations of inhibitors has reached a clinical impasse. A novel small molecule was synthesized which simultaneously targeted both MEK and PI3K pathways with in vitro IC50 values in the 50μM range. A doxycycline (Dox)-inducible transforming growth factor-α (TGFα)-transgenic mouse model was used to express lung-epithelial specific TGFα following Dox administration. ST-168 (400 mg/kg) was administered by oral gavage daily for up to 4 weeks. Control mice were treated with vehicle and treatment with vehicle or Dox alone had no significant effect on TGFα-driven fibrosis. Weekly lung CT exams allowed for assessment of fibrotic burden. Mouse studies revealed upregulation of MEK and PI3K pathways occurred with cell signaling intermediates of the p-ERK and p-AKT in the lung tissue during fibrogenesis. In association with blocking both pathways, acute studies revealed ST-168 treatment completely inhibited TGFα-mediated upregulation of the two most prevalent matrix genes in IPF: procollagen I and III. In chronic studies, remarkably, longitudinal micro-CT scanning of mice revealed reversal of pulmonary fibrosis was achieved without any drug-induced systemic toxicities. Collectively, these data demonstrate antifibrotic activity of ST-168 in the TGFα model and strongly support evaluating the efficacy of ST-168 in inhibiting and reversing pulmonary fibrosis progression. Further development of ST-168 for the treatment of fibroproliferative disease is warranted.