CLIK-148 is an oral, highly selective, irreversible inhibitor of cysteine protease that primarily targets cathepsin L. It effectively impedes the cathepsin L-dependent degradation of HMG-CoA reductase on the endoplasmic reticulum (ER) membrane. Additionally, CLIK-148 inhibits the cathepsin L-mediated processing of procholecystokinin (proCCK), leading to reduced production of CCK8. By obstructing cathepsin L degradation of type I collagen secreted by osteoclasts, CLIK-148 decreases tumor-induced bone metastasis and malignant hypercalcemia. This compound is valuable for research into bone metabolism disorders and neuropeptide processing regulation.

CLIK-148 at 100 nM to 10 μM concentration in rat liver effectively and specifically inhibits tissue Cathepsin L activity at 100 nM, shows almost no inhibition of Cathepsin B and C at 1 μM, and only weakly inhibits Cathepsin S and K at 10 μM. Additionally, CLIK-148 at 50 μM for 24 hours inhibits tissue Cathepsin L activity, blocking the conversion of proCCK to CCK9, and consequently reduces CCK8 production in pituitary AtT-20 cells. CLIK-148 at 1-10 nM for 72 hours efficiently prevents TNF-α-activated osteoclast-mediated bone collagen degradation in both human and mouse cells. Moreover, at 100 μM, CLIK-148 effectively protects HMG-CoA reductase from pathological degradation in C100 cells under necrotic damage conditions.

CLIK-148, when administered intraperitoneally at doses of 1-10 mg/kg as a single treatment, significantly inhibits cathepsin L activity in mouse liver, without affecting cathepsin B activity. At 50 mg/kg orally, administered once daily for 7 days, it effectively prevents and treats tumor-induced malignant hypercalcemia in mice. Additionally, doses of 32-128 mg/kg administered orally or intravenously once daily for 7 days effectively suppress direct bone metastasis and local bone destruction by colon cancer cells. Furthermore, doses of 100-200 mg/kg taken orally once daily for 14 days specifically inhibit the process of cancer cell metastasis to bones via the bloodstream in mice.