SIK3 Inhibitor

HG-9-91-01 is a potent and highly selective salt-inducible kinase (SIK) inhibitor with IC₅₀s of 0.92 nM, 6.6 nM and 9.6 nM for SIK1, SIK2 and SIK3 respectively.

YKL-05-099 is a salt-inducible kinase (SIK) inhibitor. YKL-05-099 binds to SIK1 and SIK3 with IC₅₀s of ~10 and ~30 nM, respectively. YKL-05-099 has slightly less potent SIK2-inhibitory (IC₅₀=40 nM).

GLPG3312 (Compound 28) is an orally active SIK inhibitor with IC₅₀ values of 2.0 nM, 0.7 nM and 0.6 nM for SIK1, SIK2 and SIK3, respectively. GLPG3312 exhibits anti-inflammatory and immunomodulatory activity in vitro on human primary myeloid cells and in vivo in mouse models. GLPG3312 has good oral bioavailability and can be used for research on inflammatory and immune diseases.

MRT199665 is a potent and ATP-competitive, selective MARK/SIK/AMPK inhibitor with IC₅₀s of 2/2/3/2 nM, 10/10 nM, and 110/12/43 nM for MARK1/MARK2/MARK3/MARK14, AMPKα1/AMPKα2, and SIK1/SIK2/SIK3, respectively. MRT199665 causes apoptosis in MEF2C-activated human acute myeloid leukemias (AML) cells. MRT199665 inhibits the phosphorylation of SIK substrate CRTC3 at S370.

ARN-3236 is an oral active and selective inhibitor of salt-inducible kinase 2 (SIK2), with IC₅₀s of <1 nM, 21.63 nM and 6.63 nM for SIK2, SIK1 and SIK3, respectively. Has anti-cancer activity.

SIK-IN-6 is a selective SIK3 inhibitor with an IC₅₀ of 15 nM. SIK-IN-6 exerts anticancer activity in acute myeloid leukemia with high MEF2C expression, but does not exhibit significant anticancer activity in acute myeloid leukemia with low MEF2C expression or in ovarian cancer. SIK-IN-6 can be used for the research of acute myeloid leukemia.

SIK2/3-IN-3 (Example 15) is a potent, selective SIK2/3 inhibitor that exhibits preferential inhibitory activity against SIK2 (IC₅₀ = 10.3 nM) and SIK3 (IC₅₀ = 0.8 nM) over SIK1 (IC₅₀ = 801 nM). SIK2/3-IN-3 can be used for the study of inflammatory diseases.

Pterosin B is an orally active indanone. Pterosin B can be obtained from Pteridium aquilinum. Pterosin B is a Sik3 signaling inhibitor. Pterosin B inhibits Klf5 expression and reduces β-amyloid deposition. Pterosin B prevents chondrocyte hypertrophy and osteoarthritis in mice. Pterosin B inhibits cardiomyocyte hypertrophy, improves cognitive impairment, and lowers blood glucose. Pterosin B can be used in research on arthritis, Alzheimer's disease, pathological cardiac hypertrophy and diabetes.

MRIA9, a chemical probe, is an ATP-competitive, pan Salt-Inducible kinase (SIK) and PAK2/3 inhibitor, with IC₅₀ values of 516 nM, 180 nM and 127 nM for SIK1, SIK2 and SIK3, respectively.

GLPG4970 is a potent, selective and orally active salt-inducible kinase 2/3 (SIK2/SIK3) dual inhibitor with IC₅₀ values of 0.3 nM and 0.7 nM. GLPG4970 has weak inhibition of hERG channel with an IC₅₀ of 29 μM. GLPG4970 can decrease TNFα release and increase IL-10 release GLPG4970 can be used for the researches of inflammation and immunology, such as colitis.

SK-124 is an orally active salt-inducible kinase (SIK) inhibitor with an IC₅₀ of 230 nM against SIK1, 4.1 nM against SIK2, and 21 nM against SIK3, exhibiting excellent kinome selectivity. SK-124 blocks SIK-mediated CRTC2 phosphorylation, promotes CRTC2 nuclear translocation, and regulates vitamin D metabolism by upregulating renal Cyp27b1 and downregulating Cyp24a1. SK-124 upregulates the expression of bone-related genes, increases serum Ca²⁺, 1,25-vitamin D and intact FGF23 levels, and suppresses endogenous PTH levels. SK-124 can be used in studies related to osteoporosis, male osteoporosis, and chronic kidney disease-mineral and bone disorder.

SIK2/3-IN-2 (compound 12, compound I-200) is a potent SIK2/3 inhibitor (SIK2 IC₅₀ = 65 nM, SIK3 IC₅₀ = 14 nM). SIK2/3-IN-2 is also a p21-activated protein kinase (PAK) 1 inhibitor with a K_i of 20.7 nM. SIK2/3-IN-2 can be used for hyperproliferative diseases and cancer research, such as Paclitaxel (HY-B0015)-resistant ovarian cancer.

SIK2/3-IN-1 (Compound 7S) is a selectively inhibitory agent of SIK2/3 with oral activity. SIK2/3-IN-1 can significantly inhibit tumor growth (without any body weight loss) in the MV4-11 AML mice CDX model. SIK2/3-IN-1 can be used in the research of MEF2C-dependent acute myeloid leukemia.

SIK1-IN-1 (Compound 27) is a selective Salt-inducible kinase 1 (SIK1) inhibitor with an IC₅₀ of 0.7  nM for SIK1 over SIK2 and SIK3. SIK1-IN-1 has no cytotoxicity against HEK293 cells and PBMCs (maximum concentration of 30 μM). SIK1-IN-1 also has potent inhibitory activities for 392 kinases, in particular tyrosine kinases, such as FGR, HCK and LYN).

SIK2-IN-5 is a SIK family kinase inhibitor, with IC₅₀ values of 0.1-1 μM against SIK2 and SIK3, and an IC₅₀ value of >1 μM against SIK1. SIK2-IN-5 inhibits the kinase activities of SIK1, SIK2 and SIK3. SIK2-IN-5 can be used in the research of ovarian cancer and breast cancer.