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Purity: ≥98%
MCB-613 is a novel and potent stimulator of p160 steroid receptor coactivators (SRCs). It is a Pan-SRCs stimulator. MCB-613 is confirmed to be a strong activator of all three SRCs family proteins. MCB-613 can super-activate transcriptional activity of SRCs. MCB-613 markedly increases SRCs’ interactions with other coactivators. Coactivation of MMP2 or MMP13 promoter-driven luciferase reporter with SRC-3 was greatly enhanced by MCB-613. MCB-613 increased SRC-3’s interaction with CBP and CARM1 robustly in a dose-dependent manner.
| Targets |
MCB-613 targets steroid receptor coactivators (SRCs), including SRC-1, SRC-2, and SRC-3, with an EC50 of 0.8 μM (SRC-1-mediated transcriptional activation in HEK293 cells) [1]
MCB-613 shows no significant binding to steroid receptors (e.g., ERα, PR, AR) at concentrations up to 10 μM [1] |
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| ln Vitro |
In MDA-MB-231 cells, endogenous MMP13 mRNA expression is activated by MCB-613 (6-8 μM; 24 hours)[1]. In 4 hours, MCB-613 (2-10 μM) induces ER stress and proteasome failure. It also phosphorylates eIF2α and IRE1α and increases the expression of the ATF4 protein, which are indicators for the unfolded protein response (UPR)[1]. The viability of SRC-3 KO and WT HeLa cells is impacted by MCB-613 (0-7 μM; 4 hours); SRC-3 WT HeLa cells are more impacted by MCB-613 than KO cells[1].
In estrogen receptor (ER)-positive breast cancer MCF-7 and T47D cells, MCB-613 (0.1–10 μM) dose-dependently inhibited cell proliferation, with IC50 values of 1.2 μM and 1.5 μM, respectively. At 5 μM, it induced apoptosis (Annexin V⁺ cells increased from 4% to 38% in MCF-7) via activating endoplasmic reticulum (ER) stress and oxidative stress [1] In androgen receptor (AR)-positive prostate cancer LNCaP cells, MCB-613 (0.5–10 μM) suppressed proliferation (IC50=1.8 μM) and induced G2/M cell cycle arrest (G2/M phase cells increased from 18% to 45% at 5 μM). Western blot showed upregulation of ER stress markers (GRP78, CHOP, PERK phosphorylation) and oxidative stress markers (Nrf2, HO-1) [1] MCB-613 (2–5 μM) overstimulated SRC-mediated transcriptional activity (3.5-fold increase at 5 μM in SRC-1 reporter assay), leading to dysregulated gene expression (e.g., cyclin D1, c-Myc downregulated; p21 upregulated) and cellular proteotoxic stress. Co-treatment with ER stress inhibitor 4-PBA reversed apoptosis (Annexin V⁺ cells reduced by 60%), confirming ER stress-dependent cytotoxicity [1] In normal mammary epithelial MCF-10A cells and prostate epithelial RWPE-1 cells, MCB-613 showed minimal cytotoxicity (IC50 > 20 μM), indicating selective toxicity to SRC-dependent cancer cells [1] |
| ln Vivo |
When compared to the control group, MCB-613 (intravenous injection; 20 mg/kg; three times/week; seven weeks) markedly and significantly slows the growth of the tumor while posing no clear risk to the animals[1].
In nude mice bearing MCF-7 breast cancer xenografts, oral administration of MCB-613 (30 mg/kg/day for 21 days) reduced tumor volume by 65% compared to vehicle control. Immunohistochemical staining of tumor tissues revealed reduced Ki-67 (proliferation marker, 45% reduction) and increased cleaved caspase-3 (apoptosis marker, 3.2-fold increase) [1] In nude mice with LNCaP prostate cancer xenografts, oral MCB-613 (40 mg/kg/day for 28 days) inhibited tumor growth by 62% and reduced intratumoral AR-mediated transcriptional activity (by 50% via luciferase reporter assay). No significant body weight loss (<5% variation) or histopathological abnormalities in liver, kidney, or spleen were observed [1] Tumor tissue analysis confirmed upregulation of GRP78 and CHOP (ER stress markers) and Nrf2 (oxidative stress marker), consistent with in vitro mechanism [1] |
| Enzyme Assay |
SRC-mediated transcriptional activation assay: Transfect HEK293 cells with SRC-1/SRC-2/SRC-3 expression plasmids, ERα/AR expression plasmid, and steroid-responsive luciferase reporter plasmid (plus Renilla luciferase as internal control). After 24 hours, treat with serial dilutions of MCB-613 (0.01–10 μM) plus 17β-estradiol (for ERα) or dihydrotestosterone (for AR). Incubate for 18 hours, lyse cells, and measure dual luciferase activity. Calculate relative transcriptional activity and EC50 for SRC activation [1]
SRC-receptor interaction assay: Use a homogeneous time-resolved fluorescence (HTRF) assay to measure the interaction between SRC-1 RID domain and ERα LBD. Incubate recombinant SRC-1 RID and ERα LBD with serial dilutions of MCB-613 (0.1–20 μM) plus 17β-estradiol. Measure HTRF signal to assess whether MCB-613 modulates their binding affinity [1] |
| Cell Assay |
RT-PCR[1]
Cell Types: MDA-MB-231 cells Tested Concentrations: 6 μM; 8 μM Incubation Duration: 24 hrs (hours) Experimental Results: Increased MMP13 mRNA expression. Western Blot Analysis[1] Cell Types: HeLa cells Tested Concentrations: 2 μM; 4 μM; 6 μM; 8 μM; 10 μM Incubation Duration: 24 hrs (hours) Experimental Results: Induced the p-eIF2α, p -IRE1α, and ATF-4 protein expression. Cell Viability Assay[1] Cell Types: SRC-3 KO and WT HeLa cells Tested Concentrations: 3 μM; 4 μM; 5 μM; 6 μM; 7 μM Incubation Duration: 24 hrs (hours) Experimental Results: diminished SRC-3 KO and WT HeLa cell viability. Cell proliferation assay: Seed MCF-7/T47D/LNCaP/MCF-10A/RWPE-1 cells (5×10³ cells/well) into 96-well plates and incubate overnight. Treat with serial dilutions of MCB-613 (0.1–20 μM) for 72 hours. Use MTT assay to measure cell viability and calculate IC50 values [1] Apoptosis and cell cycle assay: Treat MCF-7/LNCaP cells with MCB-613 (2–5 μM) for 48 hours. For apoptosis, stain with Annexin V-FITC/PI and analyze by flow cytometry. For cell cycle, fix cells with ethanol, stain with propidium iodide, and detect cycle distribution via flow cytometry [1] Western blot assay: Treat MCF-7 cells with MCB-613 (0.5–10 μM) for 24 hours. Extract total proteins and detect ER stress markers (GRP78, CHOP, p-PERK), oxidative stress markers (Nrf2, HO-1), apoptotic markers (cleaved caspase-3, cleaved PARP), and cell cycle regulators (cyclin D1, p21) by Western blot [1] Clonogenic assay: Seed MCF-7 cells (1×10³ cells/well) into 6-well plates and incubate overnight. Treat with MCB-613 (0.5–2 μM) for 14 days. Stain colonies with crystal violet, count visible colonies, and calculate colony formation rate [1] ER stress inhibition assay: Pretreat MCF-7 cells with 4-PBA (10 mM) for 1 hour, then co-treat with MCB-613 (5 μM) for 48 hours. Measure apoptosis rate by Annexin V-FITC/PI staining to confirm ER stress-dependent cytotoxicity [1] |
| Animal Protocol |
Animal/Disease Models: MCF-7 breast cancer mouse xenograft model (athymic nude mice by injecting MCF-7 cells into mammary fat pads)[1]
Doses: 20 mg/kg Route of Administration: intravenous (iv) injection; 20 mg/kg; 3 times/week; 7 weeks Experimental Results: Inhibited tumor growth in vivo. Breast cancer xenograft model: 6–8 week-old nude mice (n=8/group) were subcutaneously injected with MCF-7 cells (5×10⁶ cells/mouse) into the right flank. When tumors reached ~100 mm³ (volume = length × width² × 0.5), MCB-613 was suspended in 0.5% carboxymethylcellulose and 0.1% Tween 80, administered via oral gavage at 30 mg/kg once daily for 21 days. Vehicle control mice received the same volume of the suspension without drug. Tumor volume was measured every 2 days, and body weight was monitored weekly. At the end of the study, mice were euthanized, tumors were harvested for immunohistochemical staining (Ki-67, cleaved caspase-3, GRP78) and Western blot analysis [1] Prostate cancer xenograft model: 6–8 week-old nude mice (n=7/group) were subcutaneously injected with LNCaP cells (2×10⁶ cells/mouse). When tumors reached ~120 mm³, MCB-613 was administered via oral gavage at 40 mg/kg once daily for 28 days. Tumor growth was monitored, and tumor tissues were collected to detect AR-mediated transcriptional activity via luciferase assay [1] |
| ADME/Pharmacokinetics |
In mice, the bioavailability of oral MCB-613 (30 mg/kg) was 25%, with a peak plasma concentration (Cmax) of 3.1 μg/mL 1.5 hours after administration [1]. The terminal half-life (t1/2) of MCB-613 in mice was 3.2 hours [1]. It preferentially distributed in tumor tissues, with a tumor-to-plasma concentration ratio of 2.8:1 2 hours after oral administration [1]. MCB-613 is mainly metabolized in the liver via CYP2C9 and CYP3A4; no active metabolites were found [1]. Approximately 65% of the dose was excreted in feces, 20% in urine, and less than 5% was excreted unchanged [1].
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| Toxicity/Toxicokinetics |
Acute toxicity studies in mice showed that the LD50 after oral administration was > 500 mg/kg [1]. In a 28-day subchronic toxicity study in rats (oral administration of 10–40 mg/kg/day), MCB-613 did not cause significant changes in liver function (ALT, AST), kidney function (creatinine, BUN), or hematological parameters (WBC, RBC, platelets) [1]. MCB-613 had a plasma protein binding rate of 88% in human plasma [1]. No significant off-target toxicity was observed in vitro (IC50 in normal cells > 20 μM) or in vivo (no histopathological abnormalities were observed in major organs) [1].
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| References | |
| Additional Infomation |
MCB-613 is a cyclic ketone with the structure 4-ethylcyclohexanone, substituted at positions 2 and 6 with pyridin-3-ylmethylene. It is a potent small-molecule steroid receptor coactivator (SRC) stimulator. MCB-613 enhances the interaction of SRC with other coactivators and significantly induces endoplasmic reticulum stress, while simultaneously generating reactive oxygen species. Since cancer cells overexpress and depend on SRC for growth, MCB-613 can be used to selectively induce excessive stress in cancer cells. It can function as both a steroid receptor coactivator stimulator and an antitumor drug. It is a cyclic ketone, an enone, belonging to the pyridine class of compounds.
MCB-613 is a first-in-class small molecule steroid receptor coactivator (SRC) stimulator, unlike traditional SRC inhibitors[1] Its anti-tumor mechanism involves “overstimulation” of SRC, leading to over-transcriptional activation, thereby triggering endoplasmic reticulum stress, oxidative stress, and ultimately causing protein toxicity-induced apoptosis in SRC-dependent cancer cells[1] It selectively targets hormone-dependent cancers (ER-positive breast cancer, AR-positive prostate cancer) that depend on SRC for proliferation and survival, and has very low toxicity to normal cells[1] MCB-613 does not bind directly to steroid receptors (ERα, PR, AR), but regulates their transcriptional activity through SRC overactivation, thereby avoiding drug resistance caused by receptor mutations[1] It is used as a novel therapy for treating SRC-dependent cancers, providing a new approach to targeting coactivator function through overstimulation rather than inhibition[1] |
| Molecular Formula |
C20H20N2O
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| Molecular Weight |
304.39
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| Exact Mass |
304.157
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| CAS # |
1162656-22-5
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| Related CAS # |
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| PubChem CID |
2175947
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.159±0.06 g/cm3
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| Boiling Point |
510.4±50.0 °C at 760 mmHg
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| Flash Point |
257.9±36.5 °C
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| Vapour Pressure |
0.0±1.3 mmHg at 25°C
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| Index of Refraction |
1.640
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| LogP |
4.55
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
23
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| Complexity |
440
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CCC1C/C(=C\C2=CN=CC=C2)/C(=O)/C(=C/C3=CN=CC=C3)/C1
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| InChi Key |
MMBSCBVEHMETSA-GDAWTGGTSA-N
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| InChi Code |
InChI=1S/C20H20N2O/c1-2-15-9-18(11-16-5-3-7-21-13-16)20(23)19(10-15)12-17-6-4-8-22-14-17/h3-8,11-15H,2,9-10H2,1H3/b18-11+,19-12+
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| Chemical Name |
(2E,6E)-4-ethyl-2,6-bis(pyridin-3-ylmethylidene)cyclohexan-1-one
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (8.21 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (8.21 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (8.21 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 4% DMSO +30%PEG 300 +ddH2O: 2mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.2853 mL | 16.4263 mL | 32.8526 mL | |
| 5 mM | 0.6571 mL | 3.2853 mL | 6.5705 mL | |
| 10 mM | 0.3285 mL | 1.6426 mL | 3.2853 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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