Chemical modulators of pro-apoptotic bax and bcl-2 polypeptides

A method for identifying an organic molecule compound which activates the pro-apoptotic activity of a BAX polypeptide, the method comprising:

• a) contacting a binding site of said BAX polypeptide, wherein the binding site comprises one or more of an α1 helix, α2 helix, a loop between α1-α2, α6 helix, and select residues of α4, α5, and α8 helices, with a compound under conditions suitable for activating the pro-apoptotic activity of said BAX polypeptide;
• and
• b) detecting activation of said BAX polypeptide by said compound,
• wherein said compound binds to one or more amino acid residues corresponding to Glu17, Gln18, Met20, Lys21, Thr22, Ala24, Leu25, Leu27, Gln28, Gly29, Ile31, Gln 32, Asp33, Arg34, Ala35, Gly36, Arg37, Met38, Gly39, Gly40, Glu41, Ala 42, Leu47, Asp48, Pro49, Val50, Pro51, Gln52, Asp53, Ala54, Ser55, Thr56, Lys57, Lys58, Leu59, Ser60, Glu61, Lys64, Arg89, Phe92, Phe93, Leu122, Leu125, Thr127, Lys128, Val129, Pro130, Glu131, Leu132, Ile 133, Arg 134, Thr135, Met137, Gly138, Trp139, Leu141, Asp142, Phe143, Arg145, Glu146, Arg 147, Leu149, Gly150, Gly156, Gly157, Trp158 Asp 159, Leu161, Leu 162 of SEQ ID NO:1;
• and
• wherein the interaction of the compound with the binding site occurs at a horizontal hydrophobic groove with or without a perimeter of charged and hydrophilic residues, a superior juxta-loop, an inferior juxta-loop, or combination thereof.

A composition for treating a BCL-2 related disorder, wherein said composition comprises,

• a compound that binds to a binding site of a BCL-2 family polypeptide, wherein said binding site comprises one or more of an α1 helix, α2 helix, a loop between α1-α2, α6 helix, and select residues of α4, α5, and α8 helices, wherein said compound modulates the activity of a BCL-2 family polypeptide wherein the compound interacts with the binding site at a horizontal hydrophobic groove with or without a perimeter of charged and hydrophilic residues, a superior juxta-loop, an inferior juxta-loop, or combination thereof;
• and
• a second compound selected from an organic compound, a polypeptide and a nucleic acid or combinations thereof;
• wherein the composition binds to a binding site of said BCL-2 family polypeptide.