PROTAC ALK5 Degrader-1

C57BL/6 (Bleomycin-induced pulmonary fibrosis model)^[1]

15 mg/kg; 30 mg/kg

i.p.; daily; 14 days

Alleviated Bleomycin-induced body weight loss compared to vehicle-treated mice.
Reduced lung index by 10.6% at 15 mg/kg relative to dose-matched TP008.
Reduced fibrosis score by 9.8% at 15 mg/kg relative to dose-matched TP008, with efficacy comparable to nintedanib.
Reduced collagen positive percentage by 15.9% at 15 mg/kg relative to dose-matched TP008, restoring collagen levels toward sham control at both doses.
Reduced Collagen I fluorescence intensity by 15% and α-SMA fluorescence intensity by 20% at 15 mg/kg relative to dose-matched TP008, with efficacy comparable to nintedanib at both doses.
Reduced the proportion of lung dendritic cells (CD11c⁺ MHCII⁺) with greater efficacy than nintedanib, and attenuated bleomycin-induced accumulation of F4/80⁺ CD11b⁺ CD206⁺ macrophages with effects comparable to nintedanib, in a dose-dependent manner.
Reduced lung tissue ALK5 protein levels and suppressed downstream signaling activation (p-Smad2/3, p-AKT, p-ERK1/2) in a dose-dependent manner; showed greater suppression of p-AKT (additional 27%) and p-ERK1/2 (additional 79%) at 15 mg/kg relative to dose-matched TP008.
Showed no significant systemic toxicity: histopathology of heart, liver, spleen, and kidneys showed normal tissue architecture, and serum ALT/AST levels were not significantly different from sham controls.