852808-04-9

Hazard Information

• Chemical Properties

  Yellow Solid

• Usage

  A selective inhibitor of BCL-2, in small cell lung cancer. ABT-737 induced dramatic regressions in tumors derived from some SCLC cell lines.

• Usage

  ABT-737 is a BH3 mimetic inhibitor of Bcl-xL, Bcl-2 and Bcl-w with EC50 of 78.7 nM, 30.3 nM and 197.8 nM, respectively.

• Uses

  ABT-737 is a BH3 mimetic inhibitor of Bcl-xL, Bcl-2 and Bcl-w with EC50 of 78.7 nM, 30.3 nM and 197.8 nM, respectively.

• Uses

  A selective inhibitor of BCL-2, in small cell lung cancer. ABT-737 induced dramatic regressions in tumors derived from some SCLC cell lines.

Questions And Answer

• description

  ABT-737 is a small-molecule inhibitor of the anti-apoptotic proteins Bcl-2, Bcl-X(L) and Bcl-w, with potential pro-apoptotic and antineoplastic activities,  with an affinity two to three orders of magnitude more potent than previously reported compounds but no affinity towards less homologous proteins, such as BCL-B, MCL-1, and A1. Mechanistic studies reveal that ABT-737 does not directly initiate the apoptotic process, but enhances the effects of death signals, displaying synergistic cytotoxicity with chemotherapeutics and radiation. ABT-737 exhibits single-agent-mechanism-based killing of cells from lymphoma and small-cell lung carcinoma lines, as well as primary patient-derived cells, and in animal models, ABT-737 improves survival, causes regression of established tumors, and produces cures in a high percentage of the mice. ABT-737 binds to Bcl-2, Bcl-xL and Bcl-w with very high affinities (Ki <1 nM) and also shows a very high specificity over Mcl-1 and A1.
  ABT-737 induces apoptosis in MM cells, including those resistant to conventional therapy. Importantly, ABT-737 decreases the viability of bortezomib-, dexamethasone-(Dex) and thalidomide-refractory patient MM cells. Additionally, ABT-737 abrogates MM cell growth triggered by interleukin-6 or insulin-like growth factor-1. Mechanistic studies show that ABT-737-induced apoptosis is associated with activation of caspase-8, caspase-9 and caspase-3, followed by poly(ADP-ribose) polymerase cleavage.
  ABT-737 has shown single-agent activity against lymphoma and small-cell lung cancer as well as substantial antimyeloma activity both in vitro and in vivo. In recent studies, acute myeloid leukemia blast, origenitor, and stem cells are effectively killed by ABT-737 with normal hematopoietic cells intact. The disruption of the BCL-2/BAX complex and BAK-dependent but BIM-independent activation of the intrinsic apoptotic pathway could also be induced by ABT-737.;

• ABT-737 and ABT-263

  Both are small molecules designed to bind to the key p2 and p4 hotspots of Bcl-2 and Bcl-XL. ABT-737 as single agent exhibits effective antitumor activity in vitro against lymphoma and small-cell carcinoma cells, and also in mouse xenograft models with high expression of Bcl-2 or Bcl-XL. However, ABT-737 has low solubility and oral bioavail- ability in contrast to ABT-263, which is a second-generation ABT-737 with the same mechanism of action. Phase-I and phase-II c linical trials showed that both ABT-263 and ABT-737 were effective in CLL and small-cell lung cancer (SCLC) as a single agent. While they are useful as a single agent, ABT-737 and ABT-263 have significant synergistic effects in inducing apoptosis when combined with other antitumor drugs. ABT-263 has been shown to enhance the therapeutic effect of radiation therapy and chemotherapy for SCLC, follicular lymphoma, CLL, so on, while ABT-737 sensitized cancer cells for flavopiridol, arsenic trioxide, or fenretinide. Additional studies showed that ABT- 263 sensitized conventional agents, such as fludarabine, cyclophosphamide, and rituximab, in treating many solid tumors. However, both ABT-737 and ABT-263 can reduce platelet for targeting Bcl-Xl, which is required in maintaining the lifespan of circulating platelet, requesting the development of selective Bcl-2 inhibitors.
  Protein Kinase Inhibitors as Sensitizing Agents for Chemotherapy, Volume 4 1st Edition;

• Biological activity

  ABT-737 is a kind of BH3 mimic inhibitor, acting on Bcl-xL, Bcl-2 and Bcl-w, with the EC50 being 78.7 nM, 30.3 nM and 197.8 nM in cell-free assays; However, it has no inhibitory effect on Mcl-1, Bcl-B and Bfl-1.
  ABT737 up-regulates the expression of apoptosis-related gene Bim through JNK/c-Jun signaling pathway, and induce the apoptosis of Hela cells.
  Use MTT assay to measure the inhibitory effect of ABT-737 on the growth of human cervical cancer Hela cells; apoptosis rate was detected by flow cytometry; the expression of JNK, phospho-JNK, c-Jun and phospho-c-Jun were detected by Western blot; the mRNA expression of Bim protein was detected by RT-PCR. The activity of JNK and c-Jun was inhibited by transiently transfect of the JNK-specific inhibitor SP600125 and siRNA.
  ABT-737 can inhibit the growth of HeLa cells and induce HeLa cells to encounter apoptosis. ABT737 can activate the JNK kinase activity as well as its downstream target molecule c-Jun, further up-regulating the mRNA expression and protein expression of apoptosis-related gene Bim. ABT737-induced up-regulation of Bim and apoptosis were also blocked through inhibiting the activity or the expression of JNK or c-Jun by JNK-specific inhibitor SP600125 and siRNA targeting JNK and c-Jun.
  This information is compiled and edited by Xiao Nan from Chemicalbook.;

• In vitro study

  ABT-737 can reduce the amount of the BCL-2/BAX heterodimer while inducing the apoptosis of the HL60 cell, but have no inhibitory effect on the cell cycle distribution. ABT-737 can also induce the release of cytochrome c from mitochondria, promoting the conformational changes of BAX which was associated with apoptosis. In the leukemia model, ABT-737, at a dosage of 30 mg/kg, can block 53% of the leukemia load and significantly extend the lifespan of the mouse. ABT-737 does not lead to abnormal blood cell count and serum composition. It makes the resistant cells (Hela and MCF-7) be sensitive to ABT-737 through inactivating Mcl-1. ABT-737 can also cause the release of the BAX/BAK-dependent cytochrome c when Mcl-1 is not effective. ABT-737 can prolong the lifespan of BCL-2-bearing mice. ABT-737 is capable of replacing the BIM from the BCL2’s BH3 binding pocket, activating BAX through BIM, further inducing mitochondrial permeabilization and rapidly killing the chronic lymphocytic leukemia (CLL) cells. Noxa can positive modulates the sensitivity of H196 cells to ABT-737. ABT-737 is capable of inhibiting the proliferation of various kinds of SCLC cell lines, including NCI-H889, NCI-H1963, NCI-H1417, NCI-H146, and induces apoptosis. Recent studies have shown that ABT-737 acts on ATLL cells and significantly induced HTLV-1-infected T cell apoptosis. ABT-737, when acting on ATLL mouse model at 100 mg/kg dose, shows strong anti-cancer activity.;

• In vivo studies

  ABT-737, when acting on the leukemia model at a dose of 30 mg/kg, can inhibit the leukemia burden to up to 53%, and significantly prolong the life of the mouse. ABT-737 does not cause changes in blood cell count and plasma chemistry. ABT-737 can prolong the survival time of BCL-2-sensitized tumors. ABT-737 has a strong anti-cancer activity upon acting on the ATLL mouse model at a dose of 100 mg/kg.;

• Feature

  ABT-737 is the first-generation small molecule inhibitors of the anti-apoptotic BCL-2 family protein.;

Supplier

Related Products