Navitoclax 是有效，可口服的BCL-2抑制剂，可与BCL-xL，BCL-2， BCL-w等多种BCL-2家族蛋白结合，Ki值小于 1 nM。

Navitoclax (ABT-263) is a potent, orally bioavailable Bcl-2 family protein inhibitor that avidly binds Bcl-2, Bcl-xL, and Bcl-W (Ki< 1 nM for all three proteins).

ABT-263 is a potent, orally bioavailable Bad-like BH3 mimetic (K(i)'s of<1 nmol/L for Bcl-2, Bcl-xL, and Bcl-w). In human tumor cells, ABT-263 induces Bax translocation, cytochrome c release, and subsequent apoptosis [1]. ABT-263 was active against approximately one-half of the cell lines of the PPTP in vitro panel [2].

The oral bioavailability of ABT-263 in preclinical animal models is 20% to 50%, depending on formulation. Oral administration of ABT-263 alone induces complete tumor regressions in xenograft models of small-cell lung cancer and acute lymphoblastic leukemia [1]. ABT-263 induced significant prolongation of the EFS distribution in 9 of 35 (26%) of the solid tumor xenografts and in 5 of 6 (83%) of the evaluable ALL xenografts [2]. ABT-263 exhibited a range of antitumor activity, leading to complete tumor regression in several models. Significant regressions of tumors as large as 1 cc were also observed. The efficacy of ABT-263 was also quite durable; in several cases, minimal tumor regrowth was noted several weeks after the cessation of treatment [3].

ABT-737 and ABT-263 were synthesized as previously described. The enantiomer and BH3-only peptides were synthesized at Abbott. Binding affinities (Ki or IC50) were determined with competitive fluorescence polarization assays. The following peptide probe/protein pairs were used: f-bad (1 nmol/L) and Bcl-xL (6 nmol/L), f-Bax (1 nmol/L) and Bcl-2 (10 nmol/L), f-Bax (1 nmol/L) and Bcl-w (40 nmol/L), f-Noxa (2 nmol/L) and Mcl-1 (40 nmol/L), and f-Bax (1 nmol/L) and Bcl-2-A1 (15 nmol/L). Binding affinities for Bcl-xL were also determined using a time-resolved fluorescence resonance energy transfer assay. Bcl-xL (1 nmol/L, His tagged) was mixed with 200 nmol/L f-Bak, 1 nmol/L Tb-labeled anti-His antibody, and compound at room temperature for 30 min. Fluorescence was measured on an Envision plate reader using a 340/35 nm excitation filter and 520/525 (f-Bak) and 495/510 nm (Tb-labeled anti-His antibody) emission filters. Dissociation constants (Ki) were determined using Wang's equation [1].

Human tumor cell lines were maintained at 37°C containing 5% CO2. SCLC cell lines were cultured in RPMI 1640 with 10% fetal bovine serum (FBS), 1% sodium pyruvate, 25 mmol/L HEPES, 4.5 g/L glucose, and 1% penicillin/streptomycin. Leukemia and lymphoma cell lines were cultured in RPMI 1640 supplemented with 10% FBS and 1% penicillin/streptomycin. Cells (1 × 10^4–5 × 10^4) were treated for 48 h in 96-well culture plates in a final volume of 100 μL and cytotoxicity was assessed with the CellTiter Glo assay [1].

C.B.-17 scid-bg or C.B.-17 scid mice were implanted with 5 × 10^6 (1 × 10^6 for DoHH2) cells in 0.2 mL 50% Matrigel s.c. into the right flank. Tumor-bearing mice were size matched (～235 mm3; day 0) into treatment and control groups, ear tagged, and monitored individually. Tumor volume was measured two to three times weekly by electronic calipers (volume = length × width2 / 2). Tumor growth inhibition was calculated based on the difference in mean tumor volumes between treated and appropriate vehicle control groups. Partial response (PR) is defined as ≥50% tumor growth inhibition, and complete response (CR) is defined as nonpalpable tumor. All studies used 8 to 10 mice per group. ABT-263 was formulated in 10% ethanol, 30% polyethylene glycol 400, and 60% Phosal 50 PG and administered p.o. The other agents used [rituximab, doxorubicin, cyclophosphamide, vincristine, bortezomib, and prednisone] were administered i.p., p.o., or i.v. and formulated according to the manufacturers' recommendations. For combination studies, ABT-263 was given ～2 h before the other agents, except bortezomib, which was given ～4 h before ABT-263 [1].

923564-51-6

C47H55ClF3N5O6S3

974.61

ABT-263

Ethanol:<1 mgml
DMSO:93 mg/mL (95.4 mM)
H2O:<1 mgml
Powder: -20°C for 3 years
In solvent: -80°C for 2 years