Pin1 and Par14 Peptidyl Prolyl Isomerase Inhibitors Block Cell Proliferation

Abstract

Disruption of the parvulin family peptidyl prolyl isomerase (PPIase) Pin1 gene delays reentry into the cell cycle when quiescent primary mouse embryo fibroblasts are stimulated with serum. Since Pin1 regulates cell cycle progression, a Pin1 inhibitor would be expected to block cell proliferation. To identify such inhibitors, we screened a chemical compound library for molecules that inhibited human Pin1 PPIase activity in vitro. We found a set of compounds that inhibited Pin1 PPIase activity in vitro with low microM IC50s and inhibited the growth of several cancer lines. Among the inhibitors, PiB, diethyl-1,3,6,8-tetrahydro-1,3,6,8-tetraoxobenzo[lmn] phenanthroline-2,7-diacetate ethyl 1,3,6,8-tetrahydro-1,3,6,8-tetraoxo-benzo[lmn] phenanthroline-(2H,7H)-diacetate, had the least nonspecific toxicity. These results suggest that Pin1 inhibitors could be used as a novel type of anticancer drug that acts by blocking cell cycle progression.

PINA Is Essential for Growth and Positively Influences NIMA Function in Aspergillus nidulans

“…Although the deletion of Pin1 is not universally lethal (mice, D. melanogaster, and S. pombe), there is evidence suggesting that other isomerases can substitute for Pin1 in its absence. Drugs targeting the catalytic activity of both Pin1 and a parvulin family member, par14, have been demonstrated to block proliferation of numerous mammalian cell lines (56). Also, in S. pombe the disruption of Pin1 sensitizes the yeast to the cyclophilin inhibitor, cyclosporin A (6,57).…”

Structure and function of the human parvulins Pin1 and Par14/17

“…As functional compensation for Ess1/ Pin1 by cyclophilins A was observed in yeasts Huang et al, 2001), and the most differentially up-regulated gene/protein in Pin1 −/− MEFs was Par14, the second human parvulin representative turned out to be a likely candidate for overcoming the loss of Pin1. This idea was supported by the fact that siRNA depletion of Par14 inhibits the growth of Pin1 −/− MEF and inhibitors designed for acting on both parvulins increase the amount of S-phase cells in synchronized cell lines (Uchida et al, 2003). Moreover, Pin1 and Par14 have been found to be active in similar cellular events and pathways as summarized in Table 3.…”

“…Specific inhibitors for Par14 are missing. To our knowledge only the cell-permeable tetra-oxobenzo-phenanthroline inhibitors designed by Uchida and coworkers (Uchida et al, 2003) efficiently block PPIase activity of Pin1 as well as Par14 with comparable IC 50 values of ~1 μm in a PPIase assay. (Hennig et al, 1998) Pepti-cinnamine analogue 1 (PA1) 0.6 In cells Attacks and adds covalently to cysteine and /or lysine side chains;…”

“…Fujimori and coworkers created Pin1 knockout mice and showed that this parvulin is not essential for cell proliferation . However, in a follow up study it was demonstrated that Pin1 −/− embryonic fibroblasts (MEFs) grew slower than the corresponding control cells and entered an irreversible G0 state upon serum starvation (Uchida et al, 2003). This restricted growth of Pin1 −/− MEFs points towards a compensating mechanisms.…”

“…In cells Acts by blocking cell cycle progression; also inhibits Par14 activity in a PPIase assay (Uchida et al, 2003) (Wei et al, 2015) Aryl hetaryl ketones and thioketones (here: 11e)…”