A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action

Abstract

The prolyl isomerase PIN1, a critical modifier of multiple signalling pathways, is overexpressed in the majority of cancers and its activity strongly contributes to tumour initiation and progression. Inactivation of PIN1 function conversely curbs tumour growth and cancer stem cell expansion, restores chemosensitivity and blocks metastatic spread, thus providing the rationale for a therapeutic strategy based on PIN1 inhibition. Notwithstanding, potent PIN1 inhibitors are still missing from the arsenal of anti-cancer drugs. By a mechanism-based screening, we have identified a novel covalent PIN1 inhibitor, KPT-6566, able to selectively inhibit PIN1 and target it for degradation. We demonstrate that KPT-6566 covalently binds to the catalytic site of PIN1. This interaction results in the release of a quinone-mimicking drug that generates reactive oxygen species and DNA damage, inducing cell death specifically in cancer cells. Accordingly, KPT-6566 treatment impairs PIN1-dependent cancer phenotypes in vitro and growth of lung metastasis in vivo.

Targeting Pin1 by inhibitor API‐1 regulates microRNA biogenesis and suppresses hepatocellular carcinoma development

“…All‐trans retinoic acid induces Pin1 ablation and degrades the protein encoded by the fusion oncogene PML‐RARA, thereby blocking multiple cancer pathways . KPT‐6566 covalently binds to Pin1 and induces Pin1 degradation and DNA damage in cancer cells . Although it is undeniable that API‐1 might affect these canonical mechanisms, our data demonstrate that the anticancer phenotype of API‐1 is, at least in part, attributed to its property of modulating miRNA biogenesis.…”

“…Meanwhile, API‐1 shows inhibition of Pin1 over Pin4 (Fig. F), another parvulin family of peptidyl‐prolyl cis ‐ trans isomerases, exhibiting improved selectivity characteristics over other Pin1 inhibitors, including juglone, PiB, epigallocatechin gallate, all‐trans retinoic acid, and KPT‐6566 . Structurally, Pin1 has a conserved sequence and a distinct three‐dimensional structure for the PPIase domain.…”

Indomethacin and juglone inhibit inflammatory molecules to induce apoptosis in colon cancer cells

“…[20,21] Juglone also acts as a natural inhibitor of Pin1, which is elevated in cancerous conditions. [23,24] The present study aims to investigate the synergistic effect of indomethacin and juglone in regulating Wnt/β-catenin, Notch, and PPARγ molecular signaling mechanisms in altered inflammatory cascades associated with colon adenocarcinoma, in vitro. For example, methyl-β-cyclodextrin, a cholesterol-depleting agent has been shown to improve the efficacy of tamoxifen and doxorubicin in several cancers.…”

Discovery of a Prenylated Flavonol Derivative as a Pin1 Inhibitor to Suppress Hepatocellular Carcinoma by Modulating MicroRNA Biogenesis

“…To test the pXPO5 dependence of AF-39,w ec haracterizedt he anti-proliferative activity of AF-39 in Huh7-CTL (low XPO5 phosphorylation) and Huh7-MEKDD( high XPO5 phosphorylation) cells. [10] As in Figure S3, the activity of AF-39 was sharply reduced when pXPO5w as at al ow level, indicating the pXPO5 dependance of AF-39.U nlike ATRA [9] and KPT-6566, [7] AF-39 did not induce Pin1 degradation( Figure S4). These resultsp rovideda potentialmechanism forthe anti-cancer effect of AF-39 in HCC cells.…”

“…[6] The Juglonea nalogue KPT-6566 was reported to covalently interact with Pin1 and promote its structuralc hange and degradation,t hus inhibiting cell proliferation. [7] Teap olyphenolE GCG was found to interfere with the substrates recognition of Pin1 via blocking the cis-trans isomerization. [8] All-trans retinoic acid (ATRA) inhibits and degrades active Pin1 selectively in cancer cells by directly binding to the substrate phosphate-and proline-binding pocketsi nt he Pin1 active site.…”