Development of Novel Ecto-Nucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Inhibitors for Tumor Immunotherapy

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2022 Jul 9

PMID 35806118

Authors

Xiang Wang

Xing Lu

Daojing Yan

Yajun Zhou

Xiangshi Tan

Affiliations

Soon will be listed here.

Abstract

The cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes-TANK-binding kinase 1-interferon regulating factor 3 (cGAS-STING-TBK1-IRF3) axis is now acknowledged as the major signaling pathway in innate immune responses. However, 2',3'-cGAMP as a STING stimulator is easily recognized and degraded by ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which reduces the effect of tumor immunotherapy and promotes metastatic progression. In this investigation, the structure-based virtual screening strategy was adopted to discover eight candidate compounds containing zinc-binding quinazolin-4(3H)-one scaffold as ENPP1 inhibitors. Subsequently, these novel inhibitors targeting ENPP1 were synthesized and characterized by NMR and high-resolution mass spectra (HRMS). In bioassays, 7-fluoro-2-(((5-methoxy-1H-imidazo[4,5-b]pyridin-2-yl)thio)methyl)quina-zolin-4(3H)-one(compound 4) showed excellent activity against the ENPP1 at the molecular and cellular levels, with IC values of 0.188 μM and 0.732 μM, respectively. Additionally, compound had superior selectivity towards metastatic breast cancer cells (4T1) than towards normal cells (LO2 and 293T) in comparison with cisplatin, indicating that compound can potentially be used in metastatic breast cancer therapy. On the other hand, compound upgraded the expression levels of IFN-β in vivo by preventing the ENPP1 from hydrolyzing the cGAMP to stimulate a more potent innate immune response. Therefore, this compound might be applied to boost antitumor immunity for cancer immunotherapy. Overall, our work provides a strategy for the development of a promising drug candidate targeting ENPP1 for tumor immunotherapy.

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References

Mirgany T, Abdalla A, Arifuzzaman M, Rahman A, Al-Salem H . Quinazolin-4(3)-one based potential multiple tyrosine kinase inhibitors with excellent cytotoxicity. J Enzyme Inhib Med Chem. 2021; 36(1):2055-2067. PMC: 8462848. DOI: 10.1080/14756366.2021.1972992. View

Corrales L, McWhirter S, Dubensky Jr T, Gajewski T . The host STING pathway at the interface of cancer and immunity. J Clin Invest. 2016; 126(7):2404-11. PMC: 4922692. DOI: 10.1172/JCI86892. View

Namasivayam V, Lee S, Muller C . The promiscuous ectonucleotidase NPP1: molecular insights into substrate binding and hydrolysis. Biochim Biophys Acta Gen Subj. 2016; 1861(3):603-614. DOI: 10.1016/j.bbagen.2016.12.019. View

Tan M, Quintal L . Pembrolizumab: a novel antiprogrammed death 1 (PD-1) monoclonal antibody for treatment of metastatic melanoma. J Clin Pharm Ther. 2015; 40(5):504-507. DOI: 10.1111/jcpt.12304. View

Huan L, Tran P, Phuong C, Duc P, Anh D, Hai P . Novel 3,4-dihydro-4-oxoquinazoline-based acetohydrazides: Design, synthesis and evaluation of antitumor cytotoxicity and caspase activation activity. Bioorg Chem. 2019; 92:103202. DOI: 10.1016/j.bioorg.2019.103202. View

Fritz J, Lenardo M . Development of immune checkpoint therapy for cancer. J Exp Med. 2019; 216(6):1244-1254. PMC: 6547853. DOI: 10.1084/jem.20182395. View

Cui M, Jiang L, Goto M, Hsu P, Li L, Zhang Q . In Vivo and Mechanistic Studies on Antitumor Lead 7-Methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin-2(1H)-one and Its Modification as a Novel Class of Tubulin-Binding Tumor-Vascular Disrupting Agents. J Med Chem. 2017; 60(13):5586-5598. PMC: 6432920. DOI: 10.1021/acs.jmedchem.7b00273. View

Li J, Duran M, Dhanota N, Chatila W, Bettigole S, Kwon J . Metastasis and Immune Evasion from Extracellular cGAMP Hydrolysis. Cancer Discov. 2020; 11(5):1212-1227. PMC: 8102348. DOI: 10.1158/2159-8290.CD-20-0387. View

Gao D, Li T, Li X, Chen X, Li Q, Wight-Carter M . Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases. Proc Natl Acad Sci U S A. 2015; 112(42):E5699-705. PMC: 4620884. DOI: 10.1073/pnas.1516465112. View

10.

Zimmermann H, Zebisch M, Strater N . Cellular function and molecular structure of ecto-nucleotidases. Purinergic Signal. 2012; 8(3):437-502. PMC: 3360096. DOI: 10.1007/s11302-012-9309-4. View

11.

Wu G, Robertson D, Brooks 3rd C, Vieth M . Detailed analysis of grid-based molecular docking: A case study of CDOCKER-A CHARMm-based MD docking algorithm. J Comput Chem. 2003; 24(13):1549-62. DOI: 10.1002/jcc.10306. View

12.

Ausekle E, Ejaz S, Khan S, Ehlers P, Villinger A, Lecka J . New one-pot synthesis of N-fused isoquinoline derivatives by palladium-catalyzed C-H arylation: potent inhibitors of nucleotide pyrophosphatase-1 and -3. Org Biomol Chem. 2016; 14(48):11402-11414. DOI: 10.1039/c6ob02236g. View

13.

Ding C, Song Z, Shen A, Chen T, Zhang A . Small molecules targeting the innate immune cGAS‒STING‒TBK1 signaling pathway. Acta Pharm Sin B. 2020; 10(12):2272-2298. PMC: 7745059. DOI: 10.1016/j.apsb.2020.03.001. View

14.

Bageritz J, Puccio L, Piro R, Hovestadt V, Phillips E, Pankert T . Stem cell characteristics in glioblastoma are maintained by the ecto-nucleotidase E-NPP1. Cell Death Differ. 2014; 21(6):929-40. PMC: 4013511. DOI: 10.1038/cdd.2014.12. View

15.

Lecka J, Ben-David G, Simhaev L, Eliahu S, Oscar Jr J, Luyindula P . Nonhydrolyzable ATP analogues as selective inhibitors of human NPP1: a combined computational/experimental study. J Med Chem. 2013; 56(21):8308-20. DOI: 10.1021/jm400918s. View

16.

Carozza J, Bohnert V, Nguyen K, Skariah G, Shaw K, Brown J . Extracellular cGAMP is a cancer cell-produced immunotransmitter involved in radiation-induced anti-cancer immunity. Nat Cancer. 2021; 1(2):184-196. PMC: 7990037. DOI: 10.1038/s43018-020-0028-4. View

17.

Lu X, Cheng H, Xu Q, Tan X . Encapsulation of STING Agonist cGAMP with Folic Acid-Conjugated Liposomes Significantly Enhances Antitumor Pharmacodynamic Effect. Cancer Biother Radiopharm. 2021; 38(8):543-557. DOI: 10.1089/cbr.2020.4085. View

18.

Zhang H, Chen J . Current status and future directions of cancer immunotherapy. J Cancer. 2018; 9(10):1773-1781. PMC: 5968765. DOI: 10.7150/jca.24577. View

19.

Dennis M, Newman J, Dolezal O, Hattarki M, Surjadi R, Nuttall S . Crystal structures of human ENPP1 in apo and bound forms. Acta Crystallogr D Struct Biol. 2020; 76(Pt 9):889-898. PMC: 7466750. DOI: 10.1107/S2059798320010505. View

20.

Yan D, Xu J, Wang X, Zhang J, Zhao G, Lin Y . Spiro-Oxindole Skeleton Compounds Are Efficient Inhibitors for Indoleamine 2,3-Dioxygenase 1: An Attractive Target for Tumor Immunotherapy. Int J Mol Sci. 2022; 23(9). PMC: 9104902. DOI: 10.3390/ijms23094668. View