2nd Gen SYK Inhibitor
SYK is involved in disease pathology of immune disorders such as RA, lupus, and ITP as well as hematological cancers such as lymphoma and leukemia because it is crucial biological part of hematological development.
Its misregulation, especially of B-cell receptor pathway, could lead various type of lymphoma.
Currently, several SYK inhibitors such as cerdulatinib (GS-9973, SYK/JAK dual inhibitor) and TAK-659 (multi-kinase inhibitor) are currently in clinical development for the treatment of chronic lymphocytic leukemia and DLBCL in monotherapy or in combination (refer to the figure below). However, they may have limited application likely due to multiple kinase inhibitions. Therefore, selective SYK inhibitor is highly needed.
For example, the potency of SKI-O-576 and GS-9973 against Ba/F3 Tel-SYK model cell in the absence of mIL-3 (in green, constitutively active TEL-SYK oncogenic pathway) was 13.8 nM and 90.9 nM respectively, but that in the presence of mIL-3 (in red, JAK2/Stat bypass survival pathway) was 4328 nM and 392 nM, respectively. It suggests that GS-9973 has strong off-target effect shown in red; for GNSC-5, 313 fold and for 4.3 fold. Also, SKI-O-576 shows strong anti-proliferative potency as well as no off-target effect.