TABLE 4.

Potential PIN1 inhibitors for HCC treatment.

Drug	Covalent or non-covalent	Mechanisms of action	Clinical limitations
Sorafenib	N.A.	FDA-approved for advanced HCC treatment Inhibits RAF/MEK/ERK and VEGF receptor tyrosine kinases Suppresses PIN1-mediated Mcl-1 protein stabilization Reduces PIN1 expression by Inhibiting Rb phosphorylation Enhances apoptosis and inhibits cell proliferation	Unsatisfactory response rate with only 12 weeks survival advantage (Llovet et al., 2008) Developing sorafenib resistance or enhancing metastatic traits (Chow et al., 2013)
All-trans retinoic acid (ATRA)	Non-covalent	Induces PIN1 protein degradation Inhibits cell proliferation, migration, invasion and metastasis of HCC cells Demonstrates an enhanced anti-cancer effect by encapsulated in a slow-releasing pellet and PLLA microparticle	Poor overall survival and unsatisfactory response rate (Meyskens et al., 1998)
Arsenic trioxide (ATO)	Non-covalent	Induces PIN1 protein degradation Inhibits HCC cancer cell proliferation and xenograft tumor growth Combined with ATRA to exert a synergistic effect in inhibiting HCC cell proliferation	Ineffective in a phase II clinical study (Lin et al., 2007)
API-1	Non-covalent	Restores PIN1-impaired microRNA biosynthesis by enhancing XPO5 pre-miRNA binding ability Inhibits HCC cancer cell proliferation and xenograft tumor growth Shows an enhanced anti-cancer activity by liposomal formulation (API-LP)	No testing in clinical trial

N.A., Not applicable; FDA, US Food and Drug Administration; HCC, Hepatocellular carcinoma; Rb, Retinoblastoma; PLLA, Poly L-lactic acid; AQP9, Aquaporin 9; XPO5, Exportin-5.