STAT3 is a member of the STAT protein family. STAT3 mediates the expression of a variety of genes in response to cell stimulation. So it plays a key role in many cell processes, such as cell growth and apoptosis. Specifically, the oncogenic STAT3 signaling pathway is becoming a promising target for the treatment of multiple myeloma (MM). Besides, STAT3 has a wide range of substrate genes, including anti-apoptotic Mcl-1, Bcl-2, survivin, and cell cycle regulators (such as D-cyclin s, E2F-1). In addition, STAT3 regulates angiogenesis through the transcription of vascular endothelial growth factor (VEGF). As a nuclear transcription factor, STAT3 plays an important role in megakaryopoiesis, platelet formation, and maturation. Therefore, targeting JAK2/STAT3 signal may be an emerging strategy in the management of platelet-related diseases. SC99 is an orally active, selective STAT3 inhibitor targeting the JAK2-STAT3 pathway.
SC99 is an orally active, selective STAT3 inhibitor targeting the JAK2-STAT3 pathway.
How does brd3308 work on the target? Let’s study it together. In the beginning, SC99 is an orally active, selective STAT3 inhibitor targeting the JAK2-STAT3 pathway. Moreover, SC99 docks into the ATP-binding pocket of JAK2. Furthermore, SC99 inhibits phosphorylation of JAK2 and STAT3 with no effects on the other kinases associated with STAT3 signaling. Meanwhile, SC99 inhibits platelet activation, aggregation, and displays potent anti-myeloma, anti-thrombotic activity.
In the second place, SC99 induces MM cell death with 10 or 30 μM for 72 hours. Nonetheless, SC99 decreases the p-STAT3 level but has no effects on total STAT3 expression with 10 μM for 24 hours. Importantly, SC99 inhibits JAK2 phosphorylation in a concentration-dependent manner but does not inhibit the phosphorylation levels of AKT, ERK, mTOR, or c-Src at a concentration up to 20 μM. Importantly, SC99 inhibits collagen and thrombin (0.02 U/mL) induced phosphorylation of STAT3 in a concentration-dependent manner. Particularly, SC99 (pre-treated for 2 hours) inhibits IL-6 (50 ng/ml; for 20 min) induced STAT3 nuclear translocation in OPM2 cells.
Last but not the least, SC99 with 30 mg/kg/day for continuous 14 or 28 days by orally delayed myeloma tumor growth in xenograft mice models. Obviously, SC99 suppressed tumor growth by more than 40% in 14 days in the OPM2 model. SC99 produces an effective inhibitory effect on the phosphorylation of JAK2 and STAT3 in middle cerebral artery occlusion and reperfusion (MCAO/R) model. By the way, SC99 ameliorates neuronal apoptosis and degeneration, neurobehavioral deficits, inflammatory response, and brain edema.
All in all, SC99 is an orally active, selective STAT3 inhibitor targeting the JAK2-STAT3 pathway.
References:
Zubin Zhang, et al. Oncotarget. 2016 Feb 23;7(8):9296-308.