Myocardial infarction: MCB-613 decreases damaging remodeling inhibiting the subsequent development of heart failure

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While there are therapies to aid in overall heart health, there are very few preventative therapies for heart failure after a significant heart attack, a serious condition that has a very significant mortality.

However, researchers at Baylor College of Medicine have found a potential treatment that has shown promising results in mice.

The findings, published in the latest edition of the Proceedings of the National Academy of Sciences, showed that stimulation of a steroid receptor coactivator, SRC-3, by a molecule known as MCB-613 after a heart attack prevented the scar and maladaptive repair of heart tissue that can lead to heart failure.

“Heart failure after a significant heart attack is a leading cause of death in humans.

It often occurs over a few years; a person becomes weaker and weaker and eventually they die,” said Dr. Bert O’Malley, professor of molecular and cellular biology at Baylor and lead author of the study.

“In the mouse model, our team has been able to show that MCB-613 decreases damaging remodeling when given within hours after a myocardial infarction, thereby inhibiting the subsequent development of heart failure.”

Researchers had previously discovered and characterized MCB-613 as a small molecule stimulator for SRCs.

The family of SRCs are responsible for cellular plasticity and cell growth pathways during both normal and abnormal tissue growth.

After a heart attack, the damaged tissue scars. This results in tissue loss and increased inflammation, fibrosis and a progressive decrease in cardiac function, all of which are hallmarks of myocardial infarction-induced heart failure.

The molecule works by stimulating SRC-3, thus initiating a complex cascade of events in tissue repair and modulation of the inflammatory response.

O’Malley and his team also found that after treating the mice model with MCB-613, there were no significant signs of toxicity.

“The clinical implications of this discovery are significant. I have cared for many patients with advanced heart failure, and if we can modulate the natural history of this disease at all, we will lessen the No. 1 cause of human death and avoid a significant amount of human suffering,” said Dr. Clifford Dacso, professor of molecular and cellular biology and medicine.

“Our findings show us that this molecule acts directly on heart tissue repair and regeneration after a severe heart attack; however, more studies are needed to fully understand the safety and efficacy before we are able to use this as a therapy in humans,” O’Malley said.

“Our study shows promise to address the unmet need for treatments to prevent damage to heart tissue following a heart attack.

These findings pave the way for discovery of additional treatments to target chronic heart disease progression,” said Dr. Lisa Mullany, assistant professor of molecular and cellular biology and first author on the study.

“This is a remarkable discovery that may lead to an effective and safe treatment to prevent the progression to heart failure after a heart attack.

Heart failure is a devastating disease that is more lethal than all cancers combined, and currently there are no definitive therapies other than heart transplantation.

MCB-613 is a great candidate to help solve this huge clinical problem,” said Dr. James Martin, Vivian L. Smith professor of regenerative medicine, molecular physiology and biophysics.


MCB-613 

MCB-613 is a potent Steroid receptor coactivator SRC small molecule ‘stimulator’ (SMS), super-stimulates SRCs’ transcriptional activity.

MCB-613 increases SRCs’ interactions with other coactivators and markedly induces ER stress coupled to the generation of reactive oxygen species (ROS).

MCB-613 is a SMS that target oncogenes can be exploited as anti-cancer agents by over-stimulating the SRC oncogenic program.

MCB-613 Chemical Structure
MCB-613 Chemical Structure
CAS No. : 1162656-22-5
DescriptionMCB-613 is a potent Steroid receptor coactivator SRC small molecule ‘stimulator’ (SMS), super-stimulates SRCs’ transcriptional activity.
MCB-613 increases SRCs’ interactions with other coactivators and markedly induces ER stress coupled to the generation of reactive oxygen species (ROS).
MCB-613 is a SMS that target oncogenes can be exploited as anti-cancer agents by over-stimulating the SRC oncogenic program[1].
In VitroMCB-613 (6-8 μM; 24 hours) activates endogenous MMP13 mRNA expression in MDA-MB-231 cells[1].
MCB-613 (2-10 μM; 4 hours) leads to proteasome dysfunction and ER stress, the induction of the markers for unfolded protein response (UPR), including the phosphorylation of eIF2α and IRE1α as well as the induction of ATF4 protein expression[1].
MCB-613 (0-7 μM; 4 hours) affects SRC-3 KO and WT HeLa cell viability, SRC-3 WT HeLa cell is more affected by MCB-613 compared with KO cells[1].
MCE has not independently confirmed the accuracy of these methods.
They are for reference only.RT-PCR[1]Cell Line:MDA-MB-231 cellsConcentration:6 μM; 8 μMIncubation Time:24 hoursResult:Increased MMP13 mRNA expression.
In VivoMCB-613 (intravenous injection; 20 mg/kg; 3 times/week; 7 weeks) significantly and dramatically stalls the growth of the tumor compared with the control group and causes no obvious animal toxicity[1]MCE has not independently confirmed the accuracy of these methods.
They are for reference only.
Animal Model: MCF-7 breast cancer mouse xenograft model (athymic nude mice by injecting MCF-7 cells into mammary fat pads)[1]
Dosage:20 mg/kg
Administration:Intravenous injection; 20 mg/kg; 3 times/week; 7 weeks
Result:Inhibited tumor growth in vivo.
Molecular Weight304.39
FormulaC₂₀H₂₀N₂O
CAS No.1162656-22-5
SMILESO=C1/C(CC(CC)C/C1=C\C2=CC=CN=C2)=C/C3=CC=CN=C3
ShippingRoom temperature in continental US; may vary elsewhere.
StoragePowder-20°C3 years4°C2 yearsIn solvent-80°C6 months-20°C1 month
Solvent & SolubilityIn Vitro: 
DMSO : 50 mg/mL (164.26 mM; Need ultrasonic)H2O : < 0.1 mg/mL (insoluble)
Preparing Stock Solutions
Concentration – Solvent – Mass 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
*Please refer to the solubility information to select the appropriate solvent.
In Vivo:
1.Add each solvent one by one:  10% DMSO    40% PEG300    5% Tween-80    45% salineSolubility: ≥ 2.5 mg/mL (8.21 mM); Clear solution

2.Add each solvent one by one:  10% DMSO    90% (20% SBE-β-CD in saline)
Solubility: ≥ 2.5 mg/mL (8.21 mM); Clear solution

3.Add each solvent one by one:  10% DMSO    90% corn oil Solubility: ≥ 2.5 mg/mL (8.21 mM); Clear solution*All of the co-solvents are provided by MCE.
References[1]. Wang L, et al. Characterization of a Steroid Receptor Coactivator Small Molecule Stimulator that Overstimulates Cancer Cells and Leads to Cell Stress and Death. Cancer Cell. 2015 Aug 10;28(2):240-52.


More information: Lisa K. Mullany et al, A steroid receptor coactivator stimulator (MCB-613) attenuates adverse remodeling after myocardial infarction, Proceedings of the National Academy of Sciences (2020). DOI: 10.1073/pnas.2011614117

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