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Purity: ≥98%
Mivebresib (formerly known as ABBV-075) is a novel potent bromodomain (BRD) inhibitor that is being tested in a Phase I study for the treatment of solid tumors. Mivebresib demonstrates excellent potency in biochemical and cellular assays, advantageous exposures and half-life both in animal models and in humans, and in vivo efficacy in mouse models of cancer progression and inflammation. As a potent BET (bromodomain and extraterminal domain) inhibitor (bromodomain (BRD)-containing proteind), Mivebresib has potential antineoplastic activity. It binds bromodomains of BRD2/4/T with similar affinities (Ki of 1-2.2 nM) and highly selective for 18 bromodomain proteins tested (Kd > 1 μM; more than 600-fold selectivity vs. BRD4), but exhibits roughly 10-fold weaker potency towards BRD3 (Ki of 12.2 nM) and has moderate activity towards CREBBP (Kd = 87 μM; 54-fold selectivity vs. BRD4). In addition, potent inhibition of the BET (bromodomain and extra-terminal) family with ABBV-075 is a highly efficacious therapy in pre-clinical models of prostate cancer. The single-digit to low nanomolar anti-proliferative IC50s and potent in vivo tumor growth inhibition of ABBV-075 is mediated in part via inhibition of androgen receptor (AR)-dependent transcription.
| Targets |
Mivebresib (ABBV-075) targets BET (bromodomain and extra-terminal) family proteins [1]
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| ln Vitro |
Without significantly affecting the expression of AR proteins, ivebresib suppresses DHT-stimulated transcription of AR target genes. Apart from inhibiting transcription activation downstream of AR, Mivebresib also exhibits strong anti-MYC and anti-TMPRSS2-ETS fusion protein activity[1].
1. Mivebresib (ABBV-075) exhibited anti-proliferative activity in prostate cancer cell models with single-digit to low nanomolar IC50 values [1] 2. Gene expression profiling and qPCR results showed that Mivebresib (ABBV-075) inhibited DHT-stimulated transcription of androgen receptor (AR) target genes without significant effect on AR protein expression [1] 3. Mivebresib (ABBV-075) disrupted DHT-stimulated recruitment of BRD4 (a BET family member) to gene regulatory regions co-occupied by AR, including PSA and TMPRSS2 enhancers [1] 4. Persistent inhibition of BET family by Mivebresib (ABBV-075) led to the disassembly of AR-occupied enhancers, as indicated by reduced AR and H3K27Ac ChIP signal, and additionally downregulated enhancer RNA (eRNA) transcription [1] 5. Mivebresib (ABBV-075) displayed potent anti-proliferative activity in multiple models of resistance to the second-generation anti-androgen Enzalutamide, including models with F876L, L702H AR ligand binding domain mutations and the AR-V7 splicing variant [1] 6. In addition to blocking AR downstream transcription activation, Mivebresib (ABBV-075) was also a potent inhibitor of MYC and TMPRSS2-ETS fusion proteins [1] |
| ln Vivo |
ABBV-075 has comparable or superior efficacies to standard of care agents in flank xenograft mouse models of non-small-cell and small cell lung cancers, pancreatic, breast, prostate, head & neck cancers, multiple myeloma, diffuse large B cell lymphoma and leukemia. ABBV-075 displayed potent anti-proliferative activity in multiple models of resistance to the second generation anti-androgen Enzalutamide, including the F876L, L702H AR ligand binding domain mutations and the AR-V7 splicing variant. In addition to blocking the transcription activation downstream of AR, ABBV-075 is also a potent inhibitor of MYC and the TMPRSS2-ETS fusion proteins.
1. Mivebresib (ABBV-075) showed potent in vivo tumor growth inhibition in pre-clinical models of prostate cancer; the anti-tumor activity was mediated in part via inhibition of AR-dependent transcription [1] |
| Cell Assay |
1. Prostate cancer cells (including Enzalutamide-resistant models with F876L/L702H AR mutations or AR-V7 variant) were cultured and treated with Mivebresib (ABBV-075); cell proliferation was assessed to determine the anti-proliferative IC50 values (single-digit to low nanomolar) [1]
2. Gene expression profiling and qPCR were performed on prostate cancer cells treated with Mivebresib (ABBV-075) in the presence of DHT; the transcription levels of AR target genes and AR protein expression were detected to evaluate the effect of the drug on AR-dependent transcription [1] 3. ChIP assays were conducted to detect the recruitment of BRD4, AR and H3K27Ac to gene regulatory regions (PSA and TMPRSS2 enhancers) in DHT-stimulated prostate cancer cells treated with Mivebresib (ABBV-075); the signal intensity of ChIP was quantified to analyze the disassembly of AR-occupied enhancers [1] 4. Detection of enhancer RNA (eRNA) transcription levels in prostate cancer cells treated with Mivebresib (ABBV-075) was performed to verify the downregulation effect of the drug on eRNA [1] |
| Animal Protocol |
NA
The single-digit to low nanomolar anti-proliferative IC50s and potent in vivo tumor growth inhibition of ABBV-075 is mediated in part via inhibition of androgen receptor (AR)-dependent transcription. 1. Pre-clinical prostate cancer animal models were established to evaluate the in vivo anti-tumor activity of Mivebresib (ABBV-075); the drug was administered ; tumor growth was monitored to assess the potent tumor growth inhibition effect of the drug [1] |
| References | |
| Additional Infomation |
Mivebresib is a family inhibitor of bromodomain and terminal extradomain (BET) proteins with potential antitumor activity. After administration, mitrebib binds to the acetyllysine binding site of BRD-containing proteins, thereby preventing these proteins from interacting with acetylated histones. This disrupts chromatin remodeling, prevents the expression of certain growth-promoting genes, and leads to the inhibition of susceptible tumor cell growth.
1. Mivebresib (ABBV-075) is a novel BET family inhibitor that is currently in a phase I clinical trial for solid tumors at the time of this publication [1] 2. The development of prostate tumors and the clinical progression of castration-resistant prostate cancer (CRPC) are driven by aberrant activation of the androgen receptor (AR) transcriptional program [1] 3. Mivebresib (ABBV-075) may provide a promising treatment option for CRPC patients who are resistant to second-generation antiandrogens such as enzalutamide [1] |
| Molecular Formula |
C22H19F2N3O4S
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| Molecular Weight |
459.47
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| Exact Mass |
459.106
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| CAS # |
1445993-26-9
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| Related CAS # |
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| PubChem CID |
71600087
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| Appearance |
White to off-white solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
608.9±65.0 °C at 760 mmHg
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| Flash Point |
322.0±34.3 °C
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| Vapour Pressure |
0.0±1.7 mmHg at 25°C
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| Index of Refraction |
1.647
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| LogP |
3.91
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
32
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| Complexity |
834
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
RDONXGFGWSSFMY-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H19F2N3O4S/c1-3-32(29,30)26-14-5-7-19(31-20-6-4-13(23)10-18(20)24)16(11-14)17-12-27(2)22(28)21-15(17)8-9-25-21/h4-12,25-26H,3H2,1-2H3
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| Chemical Name |
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide
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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 (5.44 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 (5.44 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1764 mL | 10.8821 mL | 21.7642 mL | |
| 5 mM | 0.4353 mL | 2.1764 mL | 4.3528 mL | |
| 10 mM | 0.2176 mL | 1.0882 mL | 2.1764 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.
 J Med Chem.2017 Oct 26;60(20):8369-8384. |
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