Abstract
Peptidyl-prolyl cis/trans isomerase Pin1 plays a key role in amplifying and translating multiple oncogenic signaling pathways during oncogenesis. The blockade of Pin1 provided a unique way of disrupting multiple oncogenic pathways and inducing apoptosis. Aiming to develop potent Pin1 inhibitors, a series of benzimidazole derivatives were designed and synthesized. Among the derivatives, compounds 6h and 13g showed the most potent Pin1 inhibitory activity with IC50 values of 0.64 and 0.37 μM, respectively. In vitro antiproliferative assay demonstrated that compounds 6d, 6g, 6h, 6n, 6o and 7c exhibited moderate antiproliferative activity against human prostate cancer PC-3 cells. Taken together, these unique benzimidazole derivatives exhibited great potential to be further explored as potent Pin1 inhibitors with improved potency.
Highlights
Protein interacting with Never in mitosis A1 (Pin1) is a peptidyl-prolyl isomerase, which catalyzes the cis-trans isomerization of prolyl amide bonds in its substrate proteins to modulate their function and/or stability [1,2]
It was speculated that inhibiting Pin1 might be an effective way to conquer the aggressive cancers by simultaneously impacting on multiple oncogenic signaling pathways
Pin1 is overexpressed in many human cancers, including prostate, breast, lung and colon cancer, and the overexpression of Pin1 is associated with aggressive tumor progression and poor prognosis in cancer [7,8,9]
Summary
Protein interacting with Never in mitosis A1 (Pin1) is a peptidyl-prolyl isomerase, which catalyzes the cis-trans isomerization of prolyl amide bonds (pSer/Thr-Pro) in its substrate proteins to modulate their function and/or stability [1,2]. Proline-directed phosphorylation on serine or threonine is a common regulation mechanism in cells, it has been demonstrated that Pin can regulate diverse signaling processes in cell by functioning as a molecular switch and participate in cell cycle progression, apoptosis and immune responses [3,4,5]. Many research suggested that Pin played a critical role in oncogenesis by upregulation of oncogenes and downregulation of tumor suppressors [6]. It was speculated that inhibiting Pin might be an effective way to conquer the aggressive cancers by simultaneously impacting on multiple oncogenic signaling pathways. Inhibiting Pin is expected to be an effective way for fighting against tumors
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
