Development of CXCR4 modulators by virtual HTS of a novel amide-sulfamide compound library

Abstract

CXCR4 plays a crucial role in recruitment of inflammatory cells to inflammation sites at the beginning of the disease process. Modulating CXCR4 functions presents a new avenue for antiinflammatory strategies. However, using CXCR4 antagonists for a long term usage presents potential serious side effect due to their stem cell mobilizing property. We have been developing partial CXCR4 antagonists without such property. A new computer-aided drug design program, the FRESH workflow, was used for anti-CXCR4 lead compound discovery and optimization, which coupled both compound library building and CXCR4 docking screens in one campaign. Based on the designed parent framework, 30 prioritized amide-sulfamide structures were obtained after systemic filtering and docking screening. Twelve compounds were prepared from the top-30 list. Most synthesized compounds exhibited good to excellent binding affinity to CXCR4. Compounds Ig and Im demonstrated notable in vivo suppressive activity against xylene-induced mouse ear inflammation (with 56% and 54% inhibition). Western blot analyses revealed that Ig significantly blocked CXCR4/CXCL12-mediated phosphorylation of Akt. Moreover, Ig attenuated the amount of TNF-α secreted by pathogenic E. coli-infected macrophages. More importantly, Ig had no observable cytotoxicity. Our results demonstrated that FRESH virtual high throughput screening program of targeted chemical class could successfully find potent lead compounds, and

Modulators of CXCR4 and CXCR7/ACKR3 Function

“…4), is a prominent feature among CXCR4 small-molecule antagonists and serves as a starting point for ligand-based discovery of new analogs for improved potency against CXCR4. Likewise, several amidesulfonamide derivatives have CXCR4 binding properties and outperform AMD3100 in Matrigel invasion inhibition (Bai et al, 2017a(Bai et al, , 2017b.…”

The Benefits of In Silico Modeling to Identify Possible Small-Molecule Drugs and Their Off-Target Interactions

“…It is also possible that the workflow could then be extended to use machine learning to address the weaknesses of a model, based on the outcome of these comparisons and automatically build, test and validate iterative models based on the information it receives [89]. Although we have not reached this stage yet, there are again a significant number of publications in the scientific literature, which show the positive impact of workflow interfaces in a diverse range of therapeutic areas including the identification of molecules with the potential to treat cancer [90] [91,92], and those with potential to act as anti-inflammatory compounds [93]. Given the scalability of such interfaces, it does not seem unreasonable to expect their prominence to grow in small molecule drug development in response to the challenges and opportunities presented by big data.…”

Fragmentation pathways of deprotonated amide‐sulfonamide CXCR4 inhibitors investigated by ESI‐IT‐MSn, ESI‐Q‐TOF‐MS/MS and DFT calculations

“…The CXCL12/CXCR4 axis has been shown to be involved in cancer metastasis and inflammation . The amide‐sulfonamide scaffold is a novel class of CXCR4 inhibitors developed by our research group, which exhibited promising anti‐inflammatory effect both in vitro and in vivo .…”