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1.
Chem Sci ; 14(22): 5956-5964, 2023 Jun 07.
Article in English | MEDLINE | ID: mdl-37293644

ABSTRACT

Controllable activation of the innate immune adapter protein - stimulator of interferon genes (STING) pathway is a critical challenge for the clinical development of STING agonists due to the potential "on-target off-tumor" toxicity caused by systematic activation of STING. Herein, we designed and synthesized a photo-caged STING agonist 2 with a tumor cell-targeting carbonic anhydrase inhibitor warhead, which could be readily uncaged by blue light to release the active STING agonist leading to remarkable activation of STING signaling. Furthermore, compound 2 was found to preferentially target tumor cells, stimulate the STING signaling in zebrafish embryo upon photo-uncaging and to induce proliferation of macrophages and upregulation of the mRNA expression of STING as well as its downstream NF-kB and cytokines, thus leading to significant suppression of tumor cell growth in a photo-dependent manner with reduced systemic toxicity. This photo-caged agonist not only provides a powerful tool to precisely trigger STING signalling, but also represents a novel controllable STING activation strategy for safer cancer immunotherapy.

2.
Eur J Med Chem ; 238: 114480, 2022 Aug 05.
Article in English | MEDLINE | ID: mdl-35635952

ABSTRACT

Autoimmune diseases represent a class of over 80 illnesses with high incidence and prevalence and share a common pathogenesis of immune system disorders and self-attack. Over the past decade, extensive studies have demonstrated that imbalance of cGAS-STING mediated innate immune signaling is closely involved in autoimmune diseases. Over-activation of cGAS-STING pathway by mutations of STING or several exonucleases can cause accumulation of interferon and systemic inflammation. Therefore, suppression of the upregulated cGAS-STING pathway holds great potential in the treatment of human inflammatory and autoimmune diseases. Inhibitors targeting cGAS, STING and the downstream factors have been developed and pharmacologically evaluated recently. Herein, we summarize the recent advance on development of small molecular inhibitors targeting the key effectors in cGAS-STING axis as promising treatment for autoimmune diseases.


Subject(s)
Autoimmune Diseases , Membrane Proteins , Autoimmune Diseases/drug therapy , Humans , Inflammation/drug therapy , Membrane Proteins/metabolism , Nucleotidyltransferases/genetics , Nucleotidyltransferases/metabolism , Signal Transduction/physiology
3.
J Med Chem ; 65(9): 6441-6453, 2022 05 12.
Article in English | MEDLINE | ID: mdl-35466678

ABSTRACT

Piezo1 is a member of the mechanosensitive piezo ion channel family, which transduces various mechanical stimulations into electrochemical signals. Piezo1 is closely implicated in different physiological processes ranging from erythrocyte volume homeostasis to lymphatic vessel formation and bone homeostasis. Aberrant Piezo1 functions caused by gain-of-function or loss-of-function mutations are associated with various pathological conditions. Due to the significant contribution on the recognition of Piezo ion channels for sensing mechanical stress, Ardem Patapoutian received the 2021 Nobel Prize in Physiology or Medicine (jointly). Strategies of targeting and modulating Piezo1 have shown potential to produce significant therapeutic effects, thus validating Piezo1 as a promising drug target for diseases. In this Perspective, we review the cryo-EM structure, mechanogating mechanism, and physiological profiles of Piezo1, together with the latest advances in the development of its modulators. Limitations and challenges as well as future development of Piezo1 modulators are discussed as well.


Subject(s)
Ion Channels , Mechanotransduction, Cellular , Homeostasis , Ion Channels/metabolism , Lymphangiogenesis , Mutation
4.
Angew Chem Int Ed Engl ; 60(3): 1641-1645, 2021 01 18.
Article in English | MEDLINE | ID: mdl-33009704

ABSTRACT

Utilizing a chiral bicyclic imidazole organocatalyst and adopting a continuous injection process, an alternative route has been developed for the efficient synthesis of chiral phthalidyl ester prodrugs via dynamic kinetic resolution of 3-hydroxyphthalides through enantioselective acylation (up to 99 % ee). The computational studies suggest a general base catalytic mechanism differing from the widely accepted nucleophilic catalytic mechanism. The structure analysis of the key transition states shows that the CH-π interactions and not the previously considered cation/π-π interactions between the catalyst and substrate is the dominant factor giving rise to the observed stereocontrol.

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