Table 1.
Selected known Pin1 inhibitors shown to block Pin1 function by targeting various part of Pin1 protein [adapted from Zhou and Lu (49)].
| Inhibition Site | Pin1 inhibitor | Mode of discovery | IC50 | Mechanism of action | System tested | Limitation(s) |
|---|---|---|---|---|---|---|
| Pin1 active site | Juglone (103) | Low-throughput enzymatic (PPIase) assay | - | Covalent modification of Cys in the active site | in vitro | Low specificity |
| PiB (104) | Low-throughput enzymatic (PPIase) assay | 1.5 μM | - | in vitro; cell lines | Little evidence of Pin1 binding; insoluble in DMSO | |
| Pepticinnamin analogs (104) | Combinatorial synthesis | 600 nM | - | in vitro | Inconclusive evidence of Pin1 binding | |
| Cis-locked alkene peptidomimetics (87) | Structure-based design | 1.5 μM | Bind to Pin1 active site via substrate mimicking | in vitro; cell lines | - | |
| D-peptide inhibitor such as Ac-Phe-D-Thr(PO3H2)-Pip-Nal-Gln-NH2 (68, 105) | Solid phase peptide library synthesis | As low as 1 nM | Competitive inhibitor of Pin1 active site | in vitro; cell lines | Inactive in cell lines | |
| Aryl indanyl ketones (106) | Structure-based design | As low as 200 nM | Reversible inhibitor of Pin1 active site undergoing “twisted-amide” transition state | in vitro; cell lines | Binding to Pin1 not as well as hypothesized | |
| Benzothiophene (107, 108) | Structure-based design | 6 nM | Binds to Pin1 active site with high specificity | in vitro; cell lines | Potential low permeability; inactive in cell lines | |
| Phenyl imidazoles (109, 110) | Structure-based design | 830 nM | Binds to Pin1 active site | in vitro; cell lines | Some variant inactive in cell lines | |
| ATRA (all trans retinoic acid) (111) | High-throughput mechanism-based screening | 800 nM | Binds to Pin1 active site via substrate mimicking | in vitro; cell lines; mouse models; APL human patients | Moderate efficacy in humans; short half-life in humans | |
| KPT-6566 (52) | High-throughput structural- and mechanism-based screening | 1.2 μM | Covalent binding to Pin1 active site at C113 specifically | in vitro; cell lines | - | |
| Pyrimidine derivatives (102) | In-house library screening | As low as 1.68 μM | Covalent binding to the binding pocket of Pin1 active site | in vitro; cell lines | - | |
| PPIase domain | Dipentamethylene thiauram monosulfide (112) | Protease coupled enzymatic (PPIase) assay | 50 nM | Competitive inhibitor of Pin1 PPIase domain | in vitro; cell lines | Possible low specificity |
| Halogenated phenyl-isothiazolone TME-001 (113) | Real-time fluorescence detection method | 6.1 μM | Competitive inhibitor of Pin1 PPIase domain | in vitro; cell lines | Possible low specificity | |
| Cyclic peptide inhibitor Cys-Arg-Tyr-Pro- Glu-Val-Glu-Ile-Cys (113) | Phage display screening | 500 nM | Competitive inhibitor of Pin1 PPIase domain | in vitro | Cannot be used to inhibit intracellular Pin1 activity | |
| API-1 (51) | Computer-aided high-throughput virtual screening | 72.3 nM | Binds to Pin1 PPIase domain specifically | in vitro; cell lines; mouse models | - | |
| WW domain | EGCG (epigallo-catechin-3-gallate) (114) | Phenotypic association | 20 μM | Bind to both WW and PPIase domains | in vitro; cell lines; mouse models | No reports of inactivation on isolated PPIase domain |