TABLE 4

Drugs and approaches targeting Bcl-2 proteins

Reagent Principle Company/Reference Experimental Effects Clinical Trial/Status
Bcl-2 blocker Small molecule inhibitors of Bcl-2/Bcl-xL Idun/Abbott Induction of tumor cell apoptosis Preclinical
GX01 series of compounds Small molecule inhibitors binding antiapoptotic Bcl-2 proteins Gemin X Preclinical
Bcl-2 small-molecule antagonist Structure-based designed nonpeptidic Bcl-2 antagonists Structural Bioinformatics Preclinical
Tetrocarcin-A derivatives Natural fungal compound inhibitor of Bcl-2 Kyowa Hakko Kogyo Co. Inhibits mitochondrial functions regulated by Bcl-2, potentiates apoptosis Preclinical
Chelerythrine Plant alkaloid inhibiting Bcl-2/Bax interaction Chan et al., 2003 Inhibitor of Bcl-xL/Bak-BH3 interaction, induces cell death in Bcl-2 and Bcl-xL-overexpressing cells Preclinical
Antimycin A derivatives Natural and synthetic Bcl-2/Bcl-xL inhibitors Tzung et al., 2001 Bind to the BH3 pocket of Bcl-2 and Bcl-xL and induce apoptosis Preclinical
HA14—1 Chemical compound binding the Bcl-2 BH3 pocket Wang et al., 2000b Induces apoptosis in tumor cells, synergistic with drugs Preclinical
Synthetic compound Identified in an HTS, binds to the BH3 of Bcl-2 Enyedy et al., 2001 Induces cell death in Bcl-2-overexpressing cells Preclinical
Genasense Bcl-2 18-mer antisense oligonucleotide Aventis/Genta Inc. Kills drug-resistant chronic lymphocytic leukemia cells, delays development of fatal lymphoma in mice, increases dacarbazine effectiveness in melanoma models Phase-3: FDA fast-track status for melanoma, multiple myeloma, chronic lymphocytic leukemia. Phase 3 for non-small cell lung cancer, phase 2 for hormone-refractory prostate cancer
ISIS 22783 Splice-specific Bcl-x antisense oligonucleotide ISIS; Taylor et al., 1999 Redirects Bcl-x mRNA processing to proapoptotic Bcl-xS, and sensitizes tumor cells for apoptosis Preclinical
Bispecific Bcl-2/Bcl-xL antisense Antisense construct against both Bcl-2 and Bcl-xL Zangemeister-Wittke et al., 2000 Promotion of apoptosis in cell lines Preclinical
BH3 peptides from Bax, Bak, Bid or Bad BH3 peptides coupled to protein transduction domains or to fatty acids Holinger et al., 1999; Wang et al., 2000a Apoptosis induction in tumor cell lines and mouse xenografts Preclinical
SAHBs Peptidomimetic BH3-mimeticum Walensky et al., 2004 Induces Bax/Bak oligomerization, apoptosis in cell lines and growth suppression of leukemic xenografts Preclinical
BH3Is Compounds interfering with Bak-BH3/Bcl-xL interaction Degterev et al., 2001 Induction of apoptosis Preclinical