Obatoclax Mesylate

Obatoclax is an antagonist of the BCL-2 family proteins. It binds to BCL-2 with a Ki of 220 nM.

Signaling Pathways >> Autophagy >> Autophagy

Signaling Pathways >> Apoptosis >> Bcl-2 Family

Research Areas >> Cancer

Bcl-2:220 nM (Ki)

Bcl-xL:1-7 μM (Ki)

Mcl-1:1-7 μM (Ki)

Bcl-W:1-7 μM (Ki)

Bcl-B:1-7 μM (Ki)

Autophagy

Obatoclax (0, 0.5, 1, 2.5, 5, and 10 μM) effectively abrogates the growth of OCI-AmL3 cells, and similar results are seen in HL60, KG1, and U937 cells. Obatoclax also displays low-dose antiproliferative properties that are accompanied by a S/G2 cell cycle block. Obatoclax (10 μM) induces apoptosis proceeds through the intrinsic apoptotic pathway after neutralization of Mcl-1. Obatoclax synergizes with AraC and ABT-737 in inducing apoptosis in AmL cell lines. Obatoclax (250 nM) induces apoptosis and selectively inhibits colony formation of primary AmL cells[1]. Obatoclax induces cell death, with IC50 of 3.18 μM, 0.85 μM, and 0.76 μM for K1, BCPAP, and KTC-1 cells, respectively. Obatoclax also enhances cytotoxicity of Vemurafenib through inducing mixed cell death forms, loss of MOMP, suppression of mitochondrial respiration, and cellular glycolysis. Obatoclax regulates both the induction and degradation phases of authophagy, and promotes Mcl-1/Beclin-1 dependent autophagy in K1 cells[2]. Obatoclax inhibits cell proliferation and induces G1 cell-cycle arrest in a panel of human colorectal cancer cell lines, and the IC50 of cell proliferation at 72 h are 25.85, 40.69, and 40.01 nM for HCT116, HT-29, and LoVo cells, respectively. Obatoclax (0, 25, 50, 100, 200 nM) downregulates cyclin D1 to induce G1-phase arrest and consequent antiproliferation. Obatoclax (200 nM) targets cyclin D1 for proteasome-mediated degradation[3]. Obatoclax (500 nM, 1 μM) induces necrotic cell death and induces a block in autophagy, unrelated to cell death at 500 nM. Obatoclax localizes to lysosomes, affects lysosome structure and properties, but does not cause massive lysosomal permeabilization[4].

The LY3009120 monotherapy or Obatoclax+Vemurafenib (20 mg/kg/day for combination) retards tumor growth more thoroughly in subcutaneous xenograft model of thyroid cancer[2]. Obatoclax (5 mg/kg, i.p.) effectively reduces tumor growth in mice[4].

HCT116, HT-29, and LoVo cells are seeded onto six-well plates at a density of 5×104/well, followed by treatment with obatoclax (0, 50, 100, 200 nM). The numbers of cells at 24, 48, and 72 h after obatoclax treatment are harvested, resuspended, stained with trypan blue, and then counted using a Neubauer chamber.

Mice harboring [Pten, p53]thyr−/− tumors are treated with Obatoclax (5 mg/kg) via i.p. injection once every day for 6 days. Tumors are dissected and digested with Liberase. Single cell suspensions are incubated with 100 nM Lysotracker Deep Red for 30 minutes before flow cytometry analysis.

[1]. Marina Konopleva, et al. Mechanisms of Antileukemic Activity of the Novel Bcl-2 Homology Domain-3 Mimetic GX15-070 (Obatoclax). Cancer Res May 1, 2008 68; 3413

[2]. Wei WJ, et al. Obatoclax and LY3009120 Efficiently Overcome Vemurafenib Resistance in Differentiated Thyroid Cancer. Theranostics. 2017 Feb 23;7(4):987-1001.

[3]. Or CR, et al. Obatoclax, a Pan-BCL-2 Inhibitor, Targets Cyclin D1 for Degradation to Induce Antiproliferation in Human Colorectal Carcinoma Cells. Int J Mol Sci. 2016 Dec 27;18(1).

[4]. Champa D, et al. Obatoclax kills anaplastic thyroid cancer cells by inducing lysosome neutralization and necrosis. Oncotarget. 2016 Jun 7;7(23):34453-71.

[5]. Nguyen M, et al. Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19512-7. Epub 2007 Nov 26.

Venetoclax (ABT-199) | ABT-263 | S63845 | ABT-737 | A-1210477 | A-1155463 | WEHI-539 hydrochloride | A-1331852 | Bax inhibitor peptide V5 | FX 1 | Gambogic Acid | TW-37 | UMI-77 | Acetate gossypol | HA14-1