TABLE II.
Therapies Targeting the Intrinsic Pathway of Apoptosis
| Therapy | Target | Type of cancer (phase) | Company/reference |
|---|---|---|---|
| Small molecule inhibitors of Bcl-2/Bcl-xL | |||
| Obatoclax (GX15-070) | Pan-Bcl-2 inhibitor | Hematological malignancies, NSCLC, and SCLC (I–II) |
Gemin Xa/[Perez-Galan et al., 2007] |
| ABT-263 | Bcl-2, Bcl-xL, and Bcl-w |
Lymphomas, CLL, and SCLC (I) | Abbott and Genentecha/[Tuma, 2007] |
| BH3Is | Bcl-xL | Preclinical | [Degterev et al., 2001; Ray et al., 2005] |
| ABT-737 | Bcl-2, Bcl-xL, and Bcl-w |
Preclinical | Abbott Laboratories/[Oltersdorf et al., 2005] |
| Bcl-2 ASOs | |||
| Genasense (G3139) | Bcl-2 | CLL, CML, melanoma, breast cancer, and colorectal cancer (I–III) |
Genta Incorporateda/[Anon, 2007b] |
| SPC2996 | Bcl-2 | CLL (I/II) | Santaris Pharmaa/[Tilly et al., 2007] |
| Peptide-based inhibitors of Bcl-2/Bcl-xL | |||
| BH3 domain of Bak fused to a PTD |
Bcl-xL | Preclinical | [Holinger et al., 1999; Brewis et al., 2003] |
| SAHBs | Bcl-xL | Preclinical | [Walensky et al., 2004] |
| MKT-077 (lipophilic cation) | Mitochondria | Solid tumors (II—discontinued trial due to toxicity) |
[Bouchier-Hayes et al., 2005; Deocaris et al., 2007] |
| IAP inhibitors | |||
| Gene delivery of SMAC (natural IAP inhibitor) |
XIAP | Preclinical | [McNeish et al., 2003] |
| SMAC mimetics | XIAP | Preclinical | [Sun et al., 2004] |
| Capped tripeptides with unnatural amino acids |
XIAP | Preclinical | [Oost et al., 2004] |
| Non-peptidic mimetic of SMAC |
XIAP, cIAP-1 and cIAP-2 |
Preclinical | [Li et al., 2004] |
| IAP ASOs | |||
| AEG35156 (XIAP ASO) | XIAP | Pancreatic cancer, breast cancer, NSCLC, and AML (I/II) |
Aegera Therapeuticsa/[LaCasse et al., 2006] |
| LY2181308 (survivin ASO) | Survivin | Hepatocellular carcinoma (I/II) | Lilly and ISIS Pharmaceuticalsa |
NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer; CLL, chronic lymphocytic leukemia; ASO, anti-sense oligonucleotide; CML, chronic myelogenous leukemia; PTD, protein transduction domain; SAHBs, stabilized alpha-helix of BCL-2 domains; IAP, inhibitor of apoptosis protein; SMAC, second mitochondrial-derived activator of caspase; AML, acute myelogenous leukemia.