BIIB-021

Description

BIIB021 is a potent HSP90 inhibitor (IC50 = 30 nM HER-2 degradation).1 It inhibited the proliferation of MCF7 and BT474 breast cancer cell lines (IC50 = 100 nM for each). BIIB021 has shown efficacy as a therapeutic in multiple cancer models.2-5

Uses

BIIB 021 an orally available, fully synthetic small-molecule inhibitor of the heat shock protein Hsp90. Studies show that BIIB 021 adminisitration led to degradation of Hsp90 client proteins measured in tumor tissue and resulted in the inhibition of tumor growth in several human tumor xenograft models.

Definition

ChEBI: A member of the class of 2-aminopurines that is 2-aminopurine which is substituted by a chlorine at position 6 and by a (4-methoxy-3,5-dimethylpyridin-2-yl)methyl group at position 9.

Synthesis

86604-75-3

10310-21-1

848695-25-0

The general procedure for the synthesis of 6-chloro-9-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-9H-purin-2-amine (BIIB021) from 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride and 2-amino-6-chloropurine was as follows: 1. 2-Amino-6-chloropurine (10 mmol) and anhydrous potassium carbonate (12 mmol) were weighed separately and added to 25 mL of DMSO in a 50 mL round bottom flask. 2. The reaction mixture was heated to 48°C in an oil bath with continuous stirring for 30 minutes. 3. 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride (11 mmol) was weighed and added to the above reaction solution in 3 portions at 30 minute intervals. 4. After continuing the reaction at 48°C for 10 hours, the reaction temperature was adjusted to 22°C and stirred for 2 hours. 5. Upon completion of the reaction, the reaction mixture was filtered and the filtrate was retained. 6. A mixture of water and isopropanol (1:1 by volume) was added slowly and dropwise to the filtrate until the solution became turbid. 7. Place the turbid solution in a refrigerator overnight. 8. Collect the precipitate by filtration to obtain the target product BIIB021. The product 6-chloro-9-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-9H-purin-2-amine (BIIB021) was a pale yellow solid with 77% yield.

in vivo

IC 50

HSP90: 1.7 nM (Ki); HSP90: 38 nM (EC₅₀)

References

[1] SRINIVAS R. KASIBHATLA. Rationally Designed High-Affinity 2-Amino-6-halopurine Heat Shock Protein 90 Inhibitors That Exhibit Potent Antitumor Activity[J]. Journal of Medicinal Chemistry, 2007, 50 12: 2767-2778. DOI:10.1021/jm050752+
[2] KAREN LUNDGREN. BIIB021, an orally available, fully synthetic small-molecule inhibitor of the heat shock protein Hsp90.[J]. Molecular Cancer Therapeutics, 2009: 921-929. DOI:10.1158/1535-7163.mct-08-0758
[3] BORIS BÖLL. Heat shock protein 90 inhibitor BIIB021 (CNF2024) depletes NF-kappaB and sensitizes Hodgkin’s lymphoma cells for natural killer cell-mediated cytotoxicity.[J]. Clinical Cancer Research, 2009: 5108-5116. DOI:10.1158/1078-0432.ccr-09-0213
[4] HONG ZHANG. BIIB021, a synthetic Hsp90 inhibitor, has broad application against tumors with acquired multidrug resistance[J]. International Journal of Cancer, 2009, 126 5: 1226-1234. DOI:10.1002/ijc.24825
[5] XIN-TONG WANG . BIIB021, a novel Hsp90 inhibitor, sensitizes esophageal squamous cell carcinoma to radiation[J]. Biochemical and biophysical research communications, 2014, 452 4: Pages 945-950. DOI:10.1016/j.bbrc.2014.09.026