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Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
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Discovery and development of small molecule SHIP phosphatase modulators
Dennis R Viernes1, Lydia B Choi1, William G Kerr1,2,3
1Department of Chemistry, Syracuse University, Syracuse, NY, USA 13244.
Medicinal Research Reviews
|December 5, 2013
Summary
Small molecule modulators targeting the src homology 2 (SH2) containing inositol 5-phosphatase (SHIP) enzyme show therapeutic potential for diseases like cancer and diabetes. This review surveys SHIP modulators, focusing on their properties for drug development.
Area of Science:
- Cellular Biology
- Biochemistry
- Pharmacology
Background:
- Inositol phospholipids are crucial for eukaryotic cell membrane signaling.
- Phosphorylation patterns on inositols, mediated by kinases and phosphatases, govern these signals.
- The src homology 2 (SH2) containing inositol 5-phosphatase (SHIP) is central to PI3K/Akt/mTOR pathway signaling.
Purpose of the Study:
- To review the molecular basis for targeting SHIP in human diseases.
- To survey small molecule modulators of SHIP1 and SHIP2.
- To focus on the structure, potency, selectivity, and solubility of these compounds.
Main Methods:
- Literature review of cellular signaling pathways involving SHIP.
- Analysis of protein-protein interactions related to SHIP.
- Comprehensive survey of published small molecule SHIP modulators.
Main Results:
- SHIP modulation is implicated in treating cancer, inflammatory diseases, diabetes, atherosclerosis, and Alzheimer's disease.
- SHIP activity alteration may aid bone marrow transplantation and blood cell production.
- Small molecule modulators exhibit varying structures, potencies, selectivities, and solubilities.
Conclusions:
- Targeting SHIP offers therapeutic potential across diverse human diseases.
- Understanding SHIP's role in signaling pathways is key for drug development.
- Small molecule modulators of SHIP1 and SHIP2 are valuable tools for research and therapeutic applications.
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