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.

Physicochemical Properties

Molecular Formula	C22H19F2N3O4S
Molecular Weight	459.47
Exact Mass	459.106
CAS #	1445993-26-9
Related CAS #	1445993-26-9
PubChem CID	71600087
Appearance	White to off-white solid powder
Density	1.5±0.1 g/cm3
Boiling Point	608.9±65.0 °C at 760 mmHg
Flash Point	322.0±34.3 °C
Vapour Pressure	0.0±1.7 mmHg at 25°C
Index of Refraction	1.647
LogP	3.91
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	7
Rotatable Bond Count	6
Heavy Atom Count	32
Complexity	834
Defined Atom Stereocenter Count	0
InChi Key	RDONXGFGWSSFMY-UHFFFAOYSA-N
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
Chemical Name	N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide
Synonyms	ABBV075; ABBV 075; ABBV-075; Mivebresib
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

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].
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.
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.
References	[1]. Abstract 4694: ABBV-075, a novel BET family inhibitor, disrupts critical transcription programs that drive prostate cancer growth to induce potent anti-tumor activity in vitro and in vivo.
Additional Infomation	Mivebresib is an inhibitor of the Bromodomain and Extra-Terminal (BET) family of proteins, with potential antineoplastic activity. Upon administration, mivebresib binds to the acetyl-lysine binding site of BRD-containing protein(s), thereby preventing the interaction between those proteins and acetylated histones. This disrupts chromatin remodeling, prevents the expression of certain growth-promoting genes, and leads to an inhibition of cell growth in susceptible tumors.

Solubility Data

Solubility (In Vitro)

DMSO:91 mg/mL (198.05 mM) Water:<1 mg/mL Ethanol:<1 mg/mL

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.