ABT-199 --- BCL-2 inhibitor

ABT-199 is a highly potent, selective, and orally bioavailable BCL-2 inhibitor. ABT-199 has picomolar affinity for BCL-2 (Ki < 0.010 nM) and > 1000 folds selectivity over BCL-XL (Ki = 48 nM) and BCL-W (Ki = 245 nM). Therefore, ABT-199 is a much improved lead compound over the original ABT-263 (navitoclax) to avoid thrombocytopenia caused by BCL-XL inhibition. ABT-199’s cell-killing effect is selective and mechanism dependent. It can potently kill BCL-2-overexpressing FL5.12 cells (EC50 ~ 4 nM) and RS4;11 BCL-2–dependent ALL cells (EC50 ~8 nM), but showed much weaker activity against BCL-XL-overexpressing FL5.12 cells (EC50 ~261 nM) and H146 ALL cells (EC50 ~4, 260 nM). ABT-199 inhibits the growth of BCL-2–dependent human hematological tumors in vivo and spares human platelets as a single agent or in combination with rituximab and bendamustine. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicates that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2–dependent hematological cancers.

Product information

CAS Number: 1257044-40-8

Molecular Weight: 868.44

Formula: C45H50ClN7O7S

Chemical Name: (4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide)

Smiles: CC1(C)CC(C2C=CC(Cl)=CC=2)=C(CN2CCN(CC2)C2=CC(OC3C=C4C=CNC4=NC=3)=C(C=C2)C(=O)NS(=O)(=O)C2=CC(=C(C=C2)NCC2CCOCC2)[N+]([O-])=O)CC1

InChiKey: LQBVNQSMGBZMKD-UHFFFAOYSA-N

InChi: InChI=1S/C45H50ClN7O7S/c1-45(2)15-11-33(39(26-45)31-3-5-34(46)6-4-31)29-51-17-19-52(20-18-51)35-7-9-38(42(24-35)60-36-23-32-12-16-47-43(32)49-28-36)44(54)50-61(57,58)37-8-10-40(41(25-37)53(55)56)48-27-30-13-21-59-22-14-30/h3-10,12,16,23-25,28,30,48H,11,13-15,17-22,26-27,29H2,1-2H3,(H,47,49)(H,50,54)

Technical Data

Appearance: Solid Power.

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: DMSO up to 50 mM

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥12 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined.

HS Tariff Code: 382200

How to use

In Vitro:

ABT-199 was used at 0.1-1 ¦ÌM final concentration in vitro and in cellular assays.

In Vivo:

ABT-199 was orally dosed to mice at 12.5-100 mg/kg once per day in combination with rituximab and Bendamustine, and significantly reduced tumor volume.

References:

1. Fresquet V, et al. Acquired mutations in BCL2 family proteins conferring resistance to the BH3 mimetic ABT-199 in lymphoma. (2014) Blood. 123(26):4111-9.
2. Souers AJ, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. (2013) Nat Med. 19(2):202-8.
3. Roberts, A.W. et al. Selective inhibition of BCL-2 is active against chronic lymphocytic leukemia (CLL): first clinical experience with the BH3-mimetic ABT-199. Abstract 546 (European Hematology Association 2012, Amsterdam, The Netherlands, June 14¨C17, 2012).

Products are for research use only. Not for human use.

Documents