SIK3
SIK3 is an AMPK-related salt-inducible kinase whose kinase domain and UBA domain support active-conformation structure and inhibitor binding[1]. Mechanistically, cAMP/PKA signaling inhibits SIK1, SIK2, and SIK3 through phosphorylation-dependent 14-3-3 binding[2]. In skeletal biology, PTH/PTHrP signaling inhibits SIK3, reducing DEPTOR degradation and altering mTOR signaling during skeletogenesis[3]. Sik3 loss impairs chondrocyte hypertrophy in mice, linking SIK3 kinase activity to endochondral bone formation[4]. In osteoarthritis models, Sik3 deletion or pterosin B treatment inhibits chondrocyte hypertrophy and protects cartilage[5]. Compared with related isoforms, SIK3 stands out because structural SIK3-inhibitor complexes reveal ATP-site determinants for isoform selectivity[1]. Sleep genetics further identifies Sik3 mutations as regulators of wake time and inherent sleep need in mice[6]. - SIK3 regulates chondrocyte hypertrophy, mTOR signaling, sleep need, and inhibitor-selective kinase biology[1][3][4][6]. - Pterosin B provides a practical Sik3-inhibition tool for osteoarthritis and cartilage hypertrophy models[5].
References:
- [1]. Öster L, et al. The structures of salt-inducible kinase 3 in complex with inhibitors reveal determinants for binding and selectivity. J Biol Chem. 2024 May;300(5):107201. [Content Brief]
- [2]. Sonntag T, et al. 14-3-3 proteins mediate inhibitory effects of cAMP on salt-inducible kinases (SIKs). FEBS J. 2018 Feb;285(3):467-480. [Content Brief]
- [3]. Csukasi F, et al. The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling. Sci Transl Med. 2018 Sep 19;10(459):eaat9356. [Content Brief]
- [4]. Sasagawa S, et al. SIK3 is essential for chondrocyte hypertrophy during skeletal development in mice. Development. 2012 Mar;139(6):1153-63. [Content Brief]
- [5]. Yahara Y, et al. Pterosin B prevents chondrocyte hypertrophy and osteoarthritis in mice by inhibiting Sik3. Nat Commun. 2016 Mar 24;7:10959. [Content Brief]
- [6]. Funato H, et al. Forward-genetics analysis of sleep in randomly mutagenized mice. Nature. 2016 Nov 17;539(7629):378-383. [Content Brief]
All Product Categories
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SIK3 Related Products (16)
Related Products (16)
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HG-9-91-01
0 ImagesSynonyms: SIK inhibitor 1HG-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.
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YKL-05-099
0 ImagesYKL-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).
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GLPG3312
0 ImagesGLPG3312 (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.
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MRT199665
0 ImagesMRT199665 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.
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SIK-IN-6
0 ImagesCat. No.: HY-184954SIK-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.
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SIK2/3-IN-3
0 ImagesCat. No.: HY-182804CAS No.: 3069526-08-2
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Pterosin B
0 ImagesPterosin 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.
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DB1113
0 ImagesDB1113 (Example 24) is a bifunctional compound targeted protein degradation of kinases. DB1113 degrades ABL1, ABL2, BLK, CDK11B, CDK4, CSK, EPHA3, FER, GAK, LIMK1, MAP3K20, MAP4K1, MAP4K2, MAP4K3, MAP4K5, MAPK14, MAPK7, MAPK8, MAPK9, MAPKAPK2, MAPKAPK3, NLK, PDIK1L, PTK2B, RIPK1, RPS6KA1, RPS6KA3, SIK2, SIK3, STK35, TNK2, and ULK1. DB1113 can be used for research of disease or disorder mediated by aberrant kinase activity.
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MRIA9
0 ImagesMRIA9, 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.
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GLPG4970
0 ImagesGLPG4970 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.
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SK-124
0 ImagesCat. No.: HY-173191CAS No.: 2760404-50-8SK-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.
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SIK2/3-IN-2
0 ImagesCat. No.: HY-164534CAS No.: 1648864-21-4SIK2/3-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 Ki 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.
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SIK2/3-IN-1
0 ImagesCat. No.: HY-170237CAS No.: 3038863-24-7SIK2/3-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.
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SIK1-IN-1
0 ImagesCat. No.: HY-178014SIK1-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).
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SIK2-IN-5
0 ImagesCat. No.: HY-184862CAS No.: 1613711-28-6
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