HG-9-91-01 是一种有效，选择性的盐诱导型激酶 (SIK) 抑制剂，作用于 SIK1，SIK2 和 SIK3 的 IC50 分别为 0.92 nM，6.6 nM 和 9.6 nM。

98%

Store at -20℃ for one year（Powder）；Store at 2-4℃ for two weeks；Store at -20℃ for six months after dissolution.

SIK inhibitor 1

DMSO ： ≥56.8mg/mL

Salt-inducible Kinase (SIK)

HG-9-91-01 inhibits a number of protein tyrosine kinases that possess a threonine residue at the gatekeeper site, such as Src family members (Src, Lck, and Yes), BTK, and the FGF and Ephrin receptors. HG-9-91-01 demonstrates a strong correlation between the potency of SIK2 inhibition and enhanced IL-10 production. In agreement with these reports, pretreating BMDCs with HG-9-91-01, a recently described inhibitor of SIK1-3, along with several other kinases, results in concentration-dependent potentiation of zymosan-induced IL-10 production with an EC50 ~200 nM and a maximum effect similar to that observed with PGE2. HG-9-91-01 has more than a 100-fold greater potency against SIKs than AMPK (IC50=4.5 μM) in a cell-free assay. HG-9-91-01 treatment dose dependently increased mRNA expression of Pck1 and G6pc and that effect is similar in cells treated with 4 μM HG-9-91-01 or 0.1 μM glucagon. Consistent with this observation, there is also a dose-dependent increase in glucose production following HG-9-91-01 treatment.

[1]. Clark K, et al. Phosphorylation of CRTC3 by the salt-inducible kinases controls the interconversion of classically activated andregulatory macrophages. Proc Natl Acad Sci U S A. 2012 Oct 16;109(42):16986-91.

Abstract

Macrophages acquire strikingly different properties that enable them to play key roles during the initiation, propagation, and resolution of inflammation. Classically activated (M1) macrophages produce proinflammatory mediators to combat invading pathogens and respond to tissue damage in the host, whereas regulatory macrophages (M2b) produce high levels of anti-inflammatory molecules, such as IL-10, and low levels of proinflammatory cytokines, like IL-12, and are important for the resolution of inflammatory responses. A central problem in this area is to understand how the formation of regulatory macrophages can be promoted at sites of inflammation to prevent and/or alleviate chronic inflammatory and autoimmune diseases. Here, we demonstrate that the salt-inducible kinases (SIKs) restrict the formation of regulatory macrophages and that their inhibition induces striking increases in many of the characteristic markers of regulatory macrophages, greatly stimulating the production of IL-10 and other anti-inflammatory molecules. We show that SIK inhibitors elevate IL-10 production by inducing the dephosphorylation of cAMP response element-binding protein (CREB)-regulated transcriptional coactivator (CRTC) 3, its dissociation from 14-3-3 proteins and its translocation to the nucleus where it enhances a gene transcription program controlled by CREB. Importantly, the effects of SIK inhibitors on IL-10 production are lost in macrophages that express a drug-resistant mutant of SIK2. These findings identify SIKs as a key molecular switch whose inhibition reprograms macrophages to an anti-inflammatory phenotype. The remarkable effects of SIK inhibitors on macrophage function suggest that drugs that target these protein kinases may have therapeutic potential for the treatment of inflammatory and autoimmune diseases.