The family of Bcl-2 proteins plays pivotal roles in either promoting or preventing apoptosis. Bcl-2 family members contain one or more of four characteristic Bcl-2 homology (BH) domains, which are crucial for function. For example, anti-apoptotic Bcl-2 family proteins prevent death signaling by heterodimerizing with pro-death proteins at their BH3 domains. BH3I-1 is a cell permeable inhibitor that blocks the binding of BH3 peptides to Bcl-xL, inducing apoptosis. It inhibits interactions of BH3 domain-containing proteins with Bcl-xL, Bcl-2, and Bcl-W, inducing apoptosis in Bcl-2 or Bcl-W expressing cells with Ki values of 43.4 and 124 μM, respectively. BH3I-1 enhances radiation sensitivity in non-small cell lung cancer cells.
BH3I-1 is a BH3 mimetic that binds to Bcl-xL.
the bcl-2 inhibitors bh3i-1 and it analog bh3i-2 had been applied as lead compounds to find possible bcl-2 or bcl-x(l) inhibitors by using computer-assisted screening of in-house database. the identified compounds were further studied regarding their possible application as a drug. it was found that the induction of apoptosis, which was shown as number of hypodiploid cells, was increased by adding bh3i-1 and it analog bh3i-2 to bjab bcl-xl and bjab neo/mock cells. in addition, the effects of the pro-apoptotic proteins bax and bak on the induction of apoptosis via bh3i-1 and it analog bh3i-2 were investigated with a variety of knockout cell lines, and resulted showed that the presence or absence of bak or bax has no significant influence on the amount of apoptotic events induced by bh3i-1 and it analog bh3i-2 [1].
[1] füllbeck m,gebhardt n,hossbach j,daniel pt,preissner r. computer-assisted identification of small-molecule bcl-2 modulators. comput biol chem.2009 dec;33(6):451-6.
