SYK is a non-receptor tyrosine kinase. Specifically, Syk is a key element in the B cell receptor signaling pathway. Besides, Syk is also a key component of signal transduction in other immune receptors such as Fc receptors and adhesion receptors. Furthermore, Syk contains two N-terminal SH2 domains and one C-terminal tyrosine kinase domain. The activation of SYK is achieved by binding its two SRC homologous 2 (SH2) domains to phosphorylated tyrosine residues in the immune receptor tyrosine activating motif (ITAM) or ITAM like sequences in C-type lectins. Nonetheless, SYK mediates integrin signaling in neutrophils, macrophages, and platelets, P-selectin glycoprotein ligand 1 (PSGL1) signaling, and osteoclast development. Meanwhile, SYK is necessary for separating newly formed lymphatic vessels from the vascular system. Importantly, SYK plays a core role in the development of hematological malignancies such as allergic and autoimmune diseases, as well as B-cell lymphoma. Today, we will introduce an orally bioavailable, selective syk inhibitor, GS-9973 (Entospletinib).
GS-9973 is an Orally Active Syk Inhibitor for Chronic Lymphocytic Leukemia Research.
Firstly, GS-9973 (Entospletinib) is an orally bioavailable, selective Syk inhibitor with an IC50 of 7.7 nM. GS-9973 shows good bidirectional permeability across Caco-2 cell monolayers in vitro.
Secondly, GS-9973 potently inhibits BCR-mediated activation and proliferation of B-cells as well as immune-complex-stimulated cytokine production in monocytes. The combination of Idelalisib and GS-9973 synergistically inhibits CLL cell viability and further disrupts chemokine signaling.
Again, GS-9973 with 1 mg/kg by p.o. shows moderate to high bioavailability in rat and dog. In a rat collagen-induced arthritis model, GS-9973 significantly inhibits ankle inflammation. Moreover, GS-9973 shows disease-modifying activity in multiple histological measurements. Particularly, it includes inhibition of pannus formation, cartilage damage, bone resorption, and peritosteal bone formation with ED50 ranging from 1.2 to 3.9 mg/kg
Finally, GS-9973 is an orally bioavailable, selective syk inhibitor for chronic lymphocytic leukemia research.
References:
[1] Currie KS, et al. J Med Chem. 2014 May 8;57(9):3856-73.