tcsc0168 BIIB021

BIIB021 is an orally available, fully synthetic inhibitor of HSP90 with K_i and EC₅₀ of 1.7 nM and 38 nM, respectively.

IC50 & Target: Ki: 1.7 nM (HSP90)^[1]

In Vitro: BIIB021 binds in the ATP-binding pocket of Hsp90, interferes with Hsp90 chaperone function, and results in client protein degradation and tumor growth inhibition. BIIB021 inhibits tumor cell (BT474, MCF-7, N87, HT29, H1650, H1299, H69 and H82) proliferation with IC₅₀ from 0.06-0.31 μM. BIIB021 induces the degradation of Hsp90 client proteins including HER-2, Akt, and Raf-1 and up-regulated expression of the heat shock proteins Hsp70 and Hsp27^[1]. BIIB021 inhibits Hodgkin's lymphoma cells (KM-H2, L428, L540, L540cy, L591, L1236 and DEV) with IC₅₀ from 0.24-0.8 μM. BIIB021 shows low activity in lymphocytes from healthy individuals. BIIB021 inhibits the constitutive activity of NF-κB despite defective IκB. BIIB021 induces the expression of ligands for the activating NK cell receptor NKG2D on Hodgkin's lymphoma cells resulting in an increased susceptibility to NK cell-mediated killing^[2]. BIIB021 enhances the in vitro radiosensitivity of HNSCCA cell lines (UM11B and JHU12) with a corresponding reduction in the expression of key radioresponsive proteins, increases apoptotic cells and enhances G2 arrest^[3]. BIIB021 is considerably more active than 17-AAG against adrenocortical carcinoma H295R. The cytotoxic activity of BIIB021 is not influenced by loss of NQO1 or Bcl-2 overexpression, molecular lesions that do not prevent client loss but are nonetheless associated with reduced cell killing by 17-AAG. BIIB021 is also active in 17-AAG resistant cell lines (NIH-H69, MES SA Dx5, NCI-ADR-RES, Nalm6)^[4].

In Vivo: Oral administration of BIIB021 leads to tumor growth inhibition in many tumor xenograft models including N87, BT474, CWR22, U87, SKOV3 and Panc-1^[1]. BIIB021 effectively inhibits growth of L540cy tumor at a dose of 120 mg/kg^[2]. BIIB021 significantly enhances antitumor growth effect of radiation in JHU12 xenograft^[3].