ENPP1 inhibitors(Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 inhibitors), STING agonists(Stimulator of interferon genes agonists)

Therapeutic Areas

NeoplasmsSkin and Musculoskeletal Diseases

Active Indication

Triple Negative Breast Cancer

Inactive Indication-

Originator Organization

Chinese Academy of Sciences

Active Organization

Chinese Academy of Sciences

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC14H17N4O4P

InChIKeySQGOUGLKAOTADC-UIKWRGBMSA-N

CAS Registry-

100 Clinical Results associated with ENPP1 inhibitors(Chinese Academy of Sciences)

100 Translational Medicine associated with ENPP1 inhibitors(Chinese Academy of Sciences)

100 Patents (Medical) associated with ENPP1 inhibitors(Chinese Academy of Sciences)

Literatures (Medical) associated with ENPP1 inhibitors(Chinese Academy of Sciences)

01 Dec 2024·European Journal of Medicinal Chemistry

Discovery of orally bioavailable phosphonate prodrugs of potent ENPP1 inhibitors for cancer treatment

Article

Author: Jiang, Shujuan ; Xu, Yanxiao ; Zhang, Yixiang ; Yu, Songda ; Gao, Shanyun ; Zhang, Chaobo ; Tu, Wangyang ; Li, Leping ; Yu, Bing ; Li, Jingjing ; Liu, Lei ; Hou, Yingjie

Ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) is the dominant hydrolase of 2',3'-cyclic GMP-AMP (cGAMP). Inhibition of ENPP1 contributes to increased cGAMP concentration and stimulator of interferon gene (STING) activation, with the potential to boost immune response against cancer. ENPP1 is a promising therapeutic target in tumor immunotherapy. To date, orally bioavailable ENPP1 inhibitors with highly potent activity under physiological conditions have been rarely reported. Herein, we report our effort in the design and synthesis of two different series of ENPP1 inhibitors, and in the identification of a highly potent ENPP1 inhibitor 27 (IC₅₀ = 1.2 nM at pH 7.5), which significantly enhanced the cGAMP-mediated STING activity in THP-1 cells. Phosphonate compound 27 has good preclinical pharmacokinetic profiles with low plasma clearance rate in mouse, rat, and dog. It has been developed as bis-POM prodrug 36 which successfully improves the oral bioavailability of 27. In the Pan02 syngeneic mouse model of pancreatic cancer, orally administered 36 showed synergistic effect in combination with radiotherapy.

01 Sep 2024·Bioorganic & Medicinal Chemistry Letters

[1,2,4]Triazolo[1,5-a]pyrimidine derivatives: Structure-activity relationship study leading to highly selective ENPP1 inhibitors

Article

Author: Kawaguchi, Mitsuyasu ; Minami, Shohei ; Ieda, Naoya ; Nakagawa, Hidehiko

The STING (stimulator of interferon genes) pathway is one of the pathways that regulate innate immunity, and the extracellular hydrolytic enzyme ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) has been identified as its dominant negative regulator. Since activation of the innate immune system is a promising strategy for the treatment of various infectious diseases and cancers, ENPP1 inhibitors have attracted great attention as candidate drugs. We have previously identified small-molecule ENPP1 inhibitors having a [1,2,4]triazolo[1,5-a]pyrimidine scaffold by means of chemical screening using a fluorescence probe, TG-mAMP. In this study, we evaluated the structure-activity relationships of the hit and lead compounds in detail, and succeeded in developing compounds that strongly and selectively inhibit ENPP1 not only in vitro, but also in cellular systems.

14 Mar 2024·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery of Pyrido[2,3-d]pyrimidin-7-one Derivatives as Highly Potent and Efficacious Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Inhibitors for Cancer Treatment

Q1 · MEDICINE

Article

Author: Han, Yuyan ; Sun, Yaoliang ; Zhou, Yang ; Chen, Manman ; Wang, Yuxiang ; Xu, Shilin ; Xu, Lan ; Yu, Jinghua ; Meng, Linghua ; Ma, Xiaoyu ; Shi, Zihan ; Diao, Xingxing ; Li, Weiqiang ; Yu, Lei

Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is an extracellular enzyme responsible for hydrolyzing cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), the endogenous agonist for the stimulator of interferon genes (STING) pathway. Inhibition of ENPP1 can trigger STING and promote antitumor immunity, offering an attractive therapeutic target for cancer immunotherapy. Despite progress in the discovery of ENPP1 inhibitors, the diversity in chemical structures and the efficacy of the agents are far from desirable, emphasizing the demand for novel inhibitors. Herein, we describe the design, synthesis, and biological evaluation of a series of ENPP1 inhibitors based on the pyrido[2,3-d]pyrimidin-7-one scaffold. Optimization efforts led to compound 31 with significant potency in both ENPP1 inhibition and STING pathway stimulation in vitro. Notably, 31 demonstrated in vivo efficacy in a syngeneic 4T1 mouse triple negative breast cancer model. These findings provide a promising lead compound with a novel scaffold for further drug development in cancer immunotherapy.

100 Deals associated with ENPP1 inhibitors(Chinese Academy of Sciences)

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Triple Negative Breast Cancer	Preclinical	China	Chinese Academy of Sciences	22 Feb 2024

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ENPP1 inhibitors(Chinese Academy of Sciences)

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