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. 2023 Dec 12;28(24):8048.
doi: 10.3390/molecules28248048.

Structure-Activity Studies on Bis-Sulfonamide SHIP1 Activators

Shea T Meyer  1 , Sandra Fernandes  2 , Robert E Anderson  1 , Angela Pacherille  1 , Bonnie Toms  2 , William G Kerr  2 , John D Chisholm  1
Affiliations

Structure-Activity Studies on Bis-Sulfonamide SHIP1 Activators

Shea T Meyer et al. Molecules. .

Abstract

The SH2-containing inositol polyphosphate 5-phosphatase 1 (SHIP1) enzyme opposes the activity of PI3K and therefore is of interest in the treatment of inflammatory disorders. Recent results also indicate that SHIP1 promotes phagolysosomal degradation of lipids by microglia, suggesting that the enzyme may be a target for the treatment of Alzheimer's disease. Therefore, small molecules that increase SHIP1 activity may have benefits in these areas. Recently we discovered a bis-sulfonamide that increases the enzymatic activity of SHIP1. A series of similar SHIP1 activators have been synthesized and evaluated to determine structure-activity relationships and improve in vivo stability. Some new analogs have now been found with improved potency. In addition, both the thiophene and the thiomorpholine in the parent structure can be replaced by groups without a low valent sulfur atom, which provides a way to access activators that are less prone to oxidative degradation.

Keywords: SHIP1; SHIP2; activator; phosphatase; sulfonamide.

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Conflict of interest statement

The authors have patents on the use of small molecules to modulate SHIP activity to treat human disease.

Figures

Figure 1
Figure 1
The PI3K Pathway and SHIP.
Figure 2
Figure 2
Analysis of K306 structure and potential CYP oxidation sites.
Scheme 1
Scheme 1
Synthesis of analogs varying fragment B of K306.
Figure 3
Figure 3
Evaluation of SHIP1 Activation in the Malachite Green Assay. Percentage of phosphatase activity for SHIP1 and SHIP2 enzyme as determined in the malachite green assay as compared to a vehicle control (veh, DMSO) used as 100% activity. The assay was performed at 250 µM concentration for the small molecule activator with 100 µM PI(3,4,5)P3-diC8 as the substrate. Results are the mean of at least three trials. Values >100% are due to activation, while values <100% show inhibition of the enzyme.
See this image and copyright information in PMC

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