Discovery and Development of Small Molecule SHIP Phosphatase Modulators

Abstract

Inositol phospholipids play an important role in the transfer of signaling information across the cell membrane in eukaryotes. These signals are often governed by the phosphorylation patterns on the inositols, which are mediated by a number of inositol kinases and phosphatases. The src homology 2 (SH2) – containing inositol 5-phosphatase (SHIP) plays a central role in these processes, influencing signals delivered through the PI3K/Akt/mTOR pathway. SHIP modulation by small molecules has been implicated as a treatment in a number of human disease states, including cancer, inflammatory diseases, diabetes, atherosclerosis, and Alzheimer's disease. In addition, alteration of SHIP phosphatase activity may provide a means to facilitate bone marrow transplantation and increase blood cell production. This review discusses the cellular signaling pathways and protein-protein interactions that provide the molecular basis for targeting the SHIP enzyme in these disease states. In addition, a comprehensive survey of small molecule modulators of SHIP1 and SHIP2 is provided, with a focus on the structure, potency, selectivity and solubility properties of these compounds.

Hypoxia-induced p53 modulates both apoptosis and radiosensitivity via AKT

“…However, AKT can be also recruited to the plasma membrane by PI(3,4)P 2 as well as PI(3,4,5)P 3 . Therefore, it is significant that hypoxia-induced p53 also transactivates PHLDA3, which, through its pleckstrin homology domain, can bind both PI(3,4,5) P 3 and PI(3,4)P 2 , leading to efficient inactivation of AKT (32,48). This confirms that one of the principle roles of hypoxia-induced p53 is to restrict protumorigenic PI3K/AKT signaling.…”

The Crohn’s disease-associated polymorphism in ATG16L1 (rs2241880) reduces SHIP gene expression and activity in human subjects

“…28 The human gene encoding SHIP protein (INPP5D) is located at chromosome 2q37.1 and is 40 kb upstream of the gene encoding ATG16L1. 29 INPP5D and ATG16L1 are located on the same DNA strand and are transcribed in the same direction. Though there are SNPs in ATG16L1, which are in linkage disequilibrium with rs2241880, 30 there are no SNPs in INPP5D, which co-segregate with rs2241880.…”

Targeting SHP-1, 2 and SHIP Pathways: A Novel Strategy for Cancer Treatment?

“…SHIP-1 functions as a negative regulator in immunoreceptor signaling and haematopoietic progenitor cell proliferation/survival, and as an inducer of cellular apoptosis. SHIP-1 has also been implicated both as a haematopoietic tumour suppressor and activator [11,63]. SHIP-2 is ubiquitously expressed in all cell and tissue types in rodents and humans, with especially high levels of SHIP-2 being found in the heart, liver, brain, skeletal muscle, and the placenta [16,59].…”

“…However, although a potential therapeutic benefit of SHIP-1/2 agonists or inhibitors in immunomodulation or with an antitumour effect is evident, the complete switching-on/off of several signaling pathways may result in unexpected side effects; therefore, strategies to select mechanisms for modulating SHIP and the PI3K pathways would be desired [60]. In addition, small molecules activating (e.g., analogs of pelorol such as AQX-1125) or inhibiting SHIP-1/2 (e.g., quinoline small molecules such as NSC13480 and NSC305787 or 3-α-aminocholestane) had also been described [12,16,63,65], but only one, AQX-1125, is currently being studied in clinical trials.…”

“…SHIP-1 has been reported as a haematopoietic tumour suppressor and activator, and SHIP inhibition has been shown to be effective in killing cancer cells [12,16,63]. However, although a potential therapeutic benefit of SHIP-1/2 agonists or inhibitors in immunomodulation or with an antitumour effect is evident, the complete switching-on/off of several signaling pathways may result in unexpected side effects; therefore, strategies to select mechanisms for modulating SHIP and the PI3K pathways would be desired [60].…”