The STNG Pathway and drug development

Views: 83     Author: Unibest Industrial     Publish Time: 2024-01-17      Origin: Site

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A Novel Target: The STING Pathway

Infection, cancer, and cellular damages often results in mislocalized dsDNA within the cell.

The STING (Stimulator of Interferon Genes) signaling pathway is triggered through innate cyclic GMP-AMP synthase (cGAS) activation, giving the molecule cGAMP.

2,3-CGAMP 结构式

2', 3' - cGAMP molecular structure

Downstream cellular events further lead to the expression of interferons and immune responses.

CDN-driven cGAS-STING signaling pathway for inducing type 2 interferon expression

Cyclic dinucleotides, CDN-driven cGAS-STING signaling pathway for inducing type I interferon expression. src: Kong, X. et al. STING as an emerging therapeutic target for drug discovery: Perspectives from the global patent landscape. Journal of Advanced Research 44, 119–133 (2023).

Drug Development in the Clinical Trials

To modulate the STING pathway, one of the strategies is to mimic the action of the 2',3'-cGAMP, directly binding to STING.

Therefore, CDNs analogs have been developed, and examples of CDN analogs are summarised below, with ADU-S100 being the most famous one.

Drug Phase Indication
ADU-S100 Phase 2 Head and neck cancer
MK-1454 Phase 2 Squamous head and neck carcinoma
IMSA101 Phase 1/2 Solid tumor / cancer
BMS-986301 Phase 1 Solid tumor / cancer
SB 11285 Phase 1 Melanoma
TAK-676 Phase 1 Solid tumor / cancer
BI-1387446 Phase 1 Solid tumor / cancer

Zhou, Y. et al. TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res 52, D1465–D1477 (2024).

CDNs Development Efforts

Indigenous CDNs have quick clearance and low permeability; and therefore are of poor druggability. The design and optimization of CDN analog drug profiles have been a trend in the field.

CDN analog developement

Synthetic Difficulties & Unibest Chiral Platform

However, the CDNs are featured with multichiral centers and can be synthetically challenging. For instance, there can be around 28 overall steps and 15 linear steps in the synthesis of CDN STING agonists, with phospho-chirality and sugar-chirality.

Unibest's Chiral Platform has completed the synthesis of CDN fragments (compounds in the purple background above) with high chiral purity to aid your new drug development R&D.

- Cas No. 2245335-70-8

Cas No. 2245335-71-9