SK-124
Based on 1 Customer Validation
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.
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- Purity: 95.0%
- CAS No.: 2760404-50-8
- 화학식: C23H22N6O3
- 분자량:430.46
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보관:
4°C, sealed storage, away from moisture
* In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture)
To place orders, for customer services and technical support, please contact: MedChemExpress USA
Tel: 609-228-6898 E-mail: [email protected] [email protected]
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Biological Activity
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Chemical Information
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용액&용해도
- 순도&문서
- References
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Help & FAQs
Biological Activity
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SIK1 230 nM (IC50) |
SIK2 4.1 nM (IC50) |
SIK3 21 nM (IC50) |
SK-124 potently inhibits recombinant SIK2 (IC50 = 4.1 nM) and SIK3 (IC50 = 21 nM), with corresponding IC50 values in single-digit and low double-digit nanomolar range, respectively; in an in vitro radioisotope kinase assay, it exhibits 15-fold selectivity for SIK1 (IC50 = 230 nM)[2].
SK-124 (0.5 µM) exhibits superior kinome selectivity compared to non-selective SIK inhibitors. Only 9 out of 300 human kinases tested at 0.5 µM are inhibited by more than 80%, and it displays primary activity against SIK2 and SIK3[2].
SK-124 (0.5 µM) binds to intracellular SIK2 and SIK3 in HEK293T cells; in NanoBRET target binding assays, its corresponding IC50 values are 8.8 nM and 11.3 nM[2].
SK-124 (1.25-20 µM; 1 h) binds to endogenous SIK2 in murine osteocyte-like Ocy454 cells, which is confirmed by the increased thermal stability of SIK2 in cellular thermal shift assay[2].
SK-124 (78 nM-20 µM; 1 h) for immunoblotting, 90 min for nuclear translocation assay) inhibits the SIK signaling pathway in mouse osteocyte-like Ocy454 cells and human Saos2 cells by reducing the phosphorylation levels of HDAC4/HDAC5 and CRTC2 and promoting CRTC2 nuclear translocation, with an EC50 of 128 nM[2].
SK-124 (0.01-10 µM; 4 h) regulates the expression of SIK target genes in mouse osteocyte-like Ocy454 cells, reducing SOST expression and increasing TNFSF11 expression in a PTH-like manner[2].
SK-124 (10 μM; 3 h) induces nuclear translocation of CRTC2 in proximal tubule cells of H9 human embryonic stem cell-derived kidney organoids[4].
SK-124 (20 μM) reduces the phosphorylation level of CRTC2 and induces nuclear translocation of CRTC2 in opossum kidney cells[4].
SK-124 promotes the nuclear translocation of CRTC in a heterologous cell system, with an EC50 of 32 nM[4].
SK-124 (20 μM; 2-48 h) upregulates Cyp27b1 expression and increases 1,25-vitamin D production in a time-dependent manner in kidney organoids derived from H9 human embryonic stem cells[4].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:H9 human embryonic stem cell-derived kidney organoids
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Concentration:20 μM
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Incubation Time:48 h
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Result:Significantly upregulated Cyp27b1 expression relative to β-actin at 2 h (P < 0.05), 4 h (P < 0.05), 6 h (P < 0.05), 8 h (P < 0.01), and reduced expression relative to peak levels at 12 h.
Significantly increased 1,25-vitamin D levels in culture media at 24 h (P < 0.01), 36 h (P < 0.0001), and 48 h (P < 0.01) compared with vehicle.
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Cell Line:H9 human embryonic stem cell-derived kidney organoids
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Concentration:10 μM
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Incubation Time:3 h
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Result:Induced CRTC2 nuclear translocation in Lotus Tetragonolobus Lectin-positive (LTL-positive) proximal tubule cells, similar to the effect of PTH treatment.
SK-124 (40 mg/kg; i.p.; single dose) significantly increases renal Cyp27b1 expression, decreases renal Cyp24a1 expression, and elevates serum 1,25-vitamin D levels in healthy male C57BL/6 mice[4].
SK-124 (40 mg/kg; i.p.; single dose) significantly increases renal Cyp27b1 expression, decreases renal Cyp24a1 expression, and stimulates 1,25-vitamin D production in both healthy mice and mice with CKD-MBD[4].
SK-124 (2.5-40 mg/kg; p.o.; daily; 21 days) induces PTH-like effects on bone and mineral metabolism in male C57BL/6J mice, with the 40 mg/kg dose increasing trabecular bone volume fraction to ~60% and boosting bone formation rate per bone surface to ~0.008 μm3/μm2/d[2].
SK-124 (40 mg/kg; p.o.; once daily; 4 weeks) restores trabecular and cortical bone mass, improves structural bone strength, stimulates bone formation via PTH-like mechanisms, and attenuates immune-related gene expression changes in hypogonadal ORX male BALB/cJ mice[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Wild-type C57BL/6 (8-9 weeks old, equal numbers of males and females)[1]
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Dosage:40 mg/kg; 80 mg/kg; 120 mg/kg
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Administration:i.p.; single injection
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Result:Induced renal Cyp27b1 expression to ~33% of the maximal level seen with PTH treatment at 40 mg/kg for 3 h.
Did not significantly suppress renal Cyp24a1 expression at 40 mg/kg for 3 h.
Increased L5 vertebrae Fgf23 expression to a greater extent than YKL-05-099, and increased L5 vertebrae Tnfsf11 expression at 40 mg/kg for 3 h.
Recruited CRTC2 to the M1, M21a, M21b, and M21c enhancers near the Cyp27b1 gene (fold changes of +11, +14, +3, +4 respectively, vs vehicle) at 40 mg/kg for 1 h.
Dismissed CBP from the Cyp27b1 promoter region (fold change of -58 vs vehicle) at 40 mg/kg for 1 h.
Did not enrich pCREB binding at M1 or M21(a-c) enhancers near Cyp27b1 at 40 mg/kg for 1 h.
Increased pCREB binding twofold to fourfold across the promoter-proximal (PP) region and downstream enhancers (-21 to -37 kb) of the Cyp24a1 gene at 40 mg/kg for 1 h.
Dismissed CBP from downstream enhancers (-21 to -42 kb) and the PP region of Cyp24a1 at 40 mg/kg for 1 h.
Recruited CRTC2 to downstream enhancers (-21 to -42 kb) and the PP region of Cyp24a1 at 40 mg/kg for 1 h.
Increased BRD4 and RNA polymerase II occupancy near the Cyp27b1 locus at 40 mg/kg for 1 h.
Decreased BRD4 and RNA polymerase II occupancy near the Cyp24a1 locus at 40 mg/kg for 1 h.
Maximal renal Cyp27b1 expression peaked at 3 h across 40 mg/kg 0-24 h time points.
Significantly increased serum intact FGF23 (iFGF23) levels at multiple time points from 3-24 h at 40 mg/kg.
Did not alter serum PTH levels at any time point at 40 mg/kg.
Did not significantly change serum calcium or phosphate levels at 40 mg/kg.
Induced renal Cyp27b1 expression to levels significantly higher than vehicle control at 80 mg/kg and 120 mg/kg for 3 h.
Increased serum iFGF23 levels significantly compared to vehicle at 80 mg/kg and 120 mg/kg for 3 h.
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Animal Model:C57BL/6J (8-week-old male)[2]
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Dosage:2.5 mg/kg; 10 mg/kg; 40 mg/kg
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Administration:p.o.; daily; 21 days
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Result:Increased levels dose-dependently to 0.77 μM at 2.5 mg/kg, 6.49 μM at 10 mg/kg, and 20.0 μM at 40 mg/kg.
Increased serum calcium to 9.0-10.4 mg/dL, serum 1,25-vitamin D to 150-350 pmol/L, and serum FGF-23 to 400-600 pg/mL across doses, while reducing serum PTH to 50-150 pg/mL relative to vehicle.
Increased serum bone turnover markers P1NP to 50-75 ng/mL and CTX to 25-35 ng/mL at 40 mg/kg relative to vehicle.
Increased primary spongiosa bone volume fraction (PS BV/TV) to ~60% and mid-diaphyseal cortical bone tissue mineral density (Ct.TMD) to ~1160 mgHA/cm3 at 40 mg/kg relative to vehicle.
Increased osteoblast surface per bone surface (Ob.S/BS) to ~8% and osteoclast surface per bone surface (Oc.S/BS) to ~20% at 40 mg/kg relative to vehicle.
Increased matrix apposition rate (MAR) to ~1.0 μm/d and bone formation rate per bone surface (BFR/BS) to ~0.008 μm3/μm2/d at 40 mg/kg relative to vehicle, with no change in mineralizing surface per bone surface (MS/BS).
Reduced sclerostin-positive osteocytes to ~50% and cortical bone SOST gene expression to ~0.005 relative to actin at 40 mg/kg compared to vehicle.
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Animal Model:BALB/cJ mice (male, 6 weeks old at study initiation, aged to 12 weeks at sacrifice, osteoporosis induced by surgical orchiectomy)[3]
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Dosage:40 mg/kg
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Administration:p.o.; once daily; 4 weeks
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Result:Increased femoral primary spongiosa bone volume fraction (PS.BV/TV) and femoral midshaft cortical thickness (Ct.Th) in ORX mice, restoring these parameters to levels indistinguishable from sham-operated vehicle-treated controls.
Increased trabecular bone volume fraction (Tb.BV/TV) and cortical thickness (Ct.Th) in fifth lumbar vertebrae (L5) of ORX mice, with Ct.Th restored to sham levels.
Improved femoral structural properties (ultimate moment and work-to-fracture) in ORX mice, with no significant changes to apparent material properties.
Significantly increased the bone formation marker P1NP in ORX mice after 4 weeks of treatment (with a trend toward increase at 2 weeks, p=0.08), while serum CTX levels (bone resorption marker) remained unchanged.
Increased osteoblast surface (Ob.S/BS), osteoclast number per bone perimeter (N.Oc/B.Pm), and eroded surface (ES/BS) in ORX mice.
Increased mineral apposition rate (MAR) in the metaphyseal endocortical region of ORX mice; no changes in trabecular bone formation parameters (MS/BS, MAR, BFR/BS) were observed in the secondary spongiosa.
Reduced sclerostin protein levels in osteocytes and Sost gene expression in cortical bone of ORX mice, while increasing Tnfsf11 (Rankl) gene expression.
Upregulated canonical PTH target genes (Wnt4, Tnfrsf19, Nr4a1, Kcne4) and attenuated ORX-induced upregulation of immune cell-related pathways (B cell activation, mononuclear cell proliferation) in cortical bone.
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Animal Model:C57BL/6 (8-week-old male)[4]
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Dosage:40 mg/kg
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Administration:i.p.; single dose
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Result:Significantly increased renal Cyp27b1 expression relative to vehicle (P = 0.0091).
Significantly decreased renal Cyp24a1 expression relative to vehicle (P = 0.0019).
Significantly increased serum 1,25-vitamin D levels relative to vehicle (P = 0.0152).
Induced Cyp27b1 upregulation and Cyp24a1 downregulation predominantly in the S1 segment of proximal convoluted tubules, with effects similar to but more modest than PTH.
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Animal Model:C57BL/6J (male, female; inducible podocyte-specific CTCF ablation model, induced via 6.5 weeks of doxycycline administration)[4]
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Dosage:40 mg/kg
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Administration:i.p.; single dose
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Result:Significantly increased renal Cyp27b1 expression in both control (P = 0.03) and CKD-MBD (P = 0.0015) mice relative to vehicle.
Significantly decreased renal Cyp24a1 expression in both control and CKD-MBD mice relative to vehicle.
Stimulated 1,25-vitamin D production in both control and CKD-MBD mice.
Caused no significant changes in PTH, FGF23, serum calcium, urine calcium, or urine phosphate levels at the 4-hour time point.
Chemical Information
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CAS No. 2760404-50-8
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Appearance Solid
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분자량 430.46
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화학식 C23H22N6O3
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Color Off-white to light yellow
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SMILES
COC1=CC(C2=CN=C3C=C(C4=CN(C)N=C4)C=CN32)=CC(OC)=C1C5=NN=C(CC)O5
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선적
Room temperature in continental US; may vary elsewhere.
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보관
4°C, sealed storage, away from moisture
* In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture)
용액&용해도
DMSO : 100 mg/mL (232.31 mM; Need ultrasonic; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture). When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture). When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
Select the appropriate dissolution method based on your experimental animal and administration route.
- For the following dissolution methods, please ensure to first prepare a clear stock solution using an In Vitro approach and then sequentially add co-solvents:
- To ensure reliable experimental results, the clarified stock solution can be appropriately stored based on storage conditions. As for the working solution for In Vivo experiments, it is recommended to prepare freshly and use it on the same day.
- The percentages shown for the solvents indicate their volumetric ratio in the final prepared solution. If precipitation or phase separation occurs during preparation, heat and/or sonication can be used to aid dissolution.
Add each solvent one by one: 10% DMSO 40% PEG300 5% Tween-80 45% Saline
Solubility: ≥ 2.5 mg/mL (5.81 mM); Clear solution
This protocol yields a clear solution of ≥ 2.5 mg/mL (saturation unknown).
Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 mg/mL) to 400 μL PEG300, and mix evenly; then add 50 μL Tween-80 and mix evenly; then add 450 μL Saline to adjust the volume to 1 mL.
Preparation of Saline: Dissolve 0.9 g sodium chloride in ddH₂O and dilute to 100 mL to obtain a clear Saline solution.
Add each solvent one by one: 10% DMSO 90% (20% SBE-β-CD in Saline)
Solubility: ≥ 2.5 mg/mL (5.81 mM); Clear solution
This protocol yields a clear solution of ≥ 2.5 mg/mL (saturation unknown).
Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 mg/mL) to 900 μL 20% SBE-β-CD in Saline, and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C, storage for one week): 2 g SBE-β-CD powder is dissolved in 10 mL Saline, completely dissolve until clear.
Please enter the basic information of animal experiments:
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Recommended: Prepare an additional quantity of animals to account for potential losses during experiments.
Please enter your animal formula composition:
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%DMSO +
Recommended: Keep the proportion of DMSO in working solution below 2% if your animal is weak.
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%+
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+%Tween-80 + +
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%Saline +
The co-solvents required include: DMSO, . All of co-solvents are available by MedChemExpress (MCE). , Tween 80. All of co-solvents are available by MedChemExpress (MCE).
Working solution concentration: 0.22 mg/mL
Method for preparing stock solution: mg drug dissolved in μL DMSO. Stock solution concentration: mg/mL. * In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture)
1. Take μL DMSO stock solution;
2. Add μL .
μL , mix evenly;
3. Then add μL Tween 80, mix evenly;
4. Then add μL
Please ensure that the stock solution in the first step is dissolved to a clear state, and add co-solvents in sequence. You can use ultrasonic heating (ultrasonic cleaner, recommended frequency 20-40 kHz), vortexing, etc. to assist dissolution.
순도&문서
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Data Sheet (295 KB)
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SDS (252 KB)
- English - EN (252 KB)
- Français - FR (252 KB)
- Deutsch - DE (252 KB)
- Norwegian - NO (252 KB)
- Español - ES (252 KB)
- Swedish - SV (252 KB)
- Italian - IT (252 KB)
- Korean - KR (252 KB)
- Portuguese - PT (252 KB)
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Handling Instructions (2659 KB)
References
[1]. Meyer MB, et al. Rapid genomic changes by mineralotropic hormones and kinase SIK inhibition drive coordinated renal Cyp27b1 and Cyp24a1 expression via CREB modules. The Journal of biological chemistry. 2022 Nov;298(11):102559. [Content Brief]
[2]. Sato T, et al. Structure-based design of selective, orally available salt-inducible kinase inhibitors that stimulate bone formation in mice. Proceedings of the National Academy of Sciences of the United States of America. 2022 Dec 13;119(50):e2214396119. [Content Brief]
[3]. Choi RB, et al. The orally available SIK2/SIK3 inhibitor SK-124 increases bone mass in hypogonadal male mice. JBMR plus. 2026 Apr;10(4):ziag032. [Content Brief]
[4]. Yoon SH, et al. A parathyroid hormone/salt-inducible kinase signaling axis controls renal vitamin D activation and organismal calcium homeostasis. The Journal of clinical investigation. 2023 May 01;133(9):e163627. [Content Brief]
Complete Stock Solution Preparation Table
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture). When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
| Optional Solvent | Concentration Solvent Mass | 1 mg | 5 mg | 10 mg | 25 mg |
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| DMSO | 1 mM | 2.3231 mL | 11.6155 mL | 23.2310 mL | 58.0774 mL |
| 5 mM | 0.4646 mL | 2.3231 mL | 4.6462 mL | 11.6155 mL | |
| 10 mM | 0.2323 mL | 1.1615 mL | 2.3231 mL | 5.8077 mL | |
| 15 mM | 0.1549 mL | 0.7744 mL | 1.5487 mL | 3.8718 mL | |
| 20 mM | 0.1162 mL | 0.5808 mL | 1.1615 mL | 2.9039 mL | |
| 25 mM | 0.0929 mL | 0.4646 mL | 0.9292 mL | 2.3231 mL | |
| 30 mM | 0.0774 mL | 0.3872 mL | 0.7744 mL | 1.9359 mL | |
| 40 mM | 0.0581 mL | 0.2904 mL | 0.5808 mL | 1.4519 mL | |
| 50 mM | 0.0465 mL | 0.2323 mL | 0.4646 mL | 1.1615 mL | |
| 60 mM | 0.0387 mL | 0.1936 mL | 0.3872 mL | 0.9680 mL | |
| 80 mM | 0.0290 mL | 0.1452 mL | 0.2904 mL | 0.7260 mL | |
| 100 mM | 0.0232 mL | 0.1162 mL | 0.2323 mL | 0.5808 mL |
SK-124 Related Classifications
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