Small molecule inhibitors of Bcl-2, an anti-apoptotic protein, for cancer treatment.
- Developed specifically to target the BH4 homology domain of Bcl-2 in order to improve binding affinity and anti-tumor efficacy over other Bcl-2 inhibitors.
- Compounds may simultaneously suppress a wider range of anti-apoptotic proteins than currently available Bcl-2 inhibitors.
Bcl-2, a protein overexpressed in many cancers, including lung cancer, makes cancer cells more resistant to chemotherapy. Small molecule inhibitors of Bcl-2 recorded $8.3B in global sales in 2011. None of these small molecule inhibitors on the market targets the BH4 domain that is required for the protein's anti-apoptotic function. Development of more effective drugs that act through basic molecular mechanisms (i.e., apoptosis) to overcome radiation- or chemo-resistance in cancer patients is essential to improve the prognosis of patients with various types of cancer.
Emory researchers have developed several BH4 domain-specific small molecule inhibitors of the Bcl2 family. The BH4 domain, conserved in major anti-apoptotic proteins (e.g., Bcl2, Bcl-XL, Mcl-1 etc.), is associated with radio- or chemo-resistance of various cancers. Preliminary findings indicate that most human lung cancer cell lines are more sensitive to the novel Emory compounds compared to ABT-737 (a BH3 mimetic, small molecule Bcl2 inhibitor currently in Phase II clinical trials). ABT-737 binds Bcl-2 and Bcl-XL with high affinity, but not MCl-1. Our compounds can bind all three anti-apoptotic proteins efficiently through their conserved BH4 domains. A major challenge in improving outcomes of patients with lung cancer is the development of acquired radioresistance. Our novel Bcl2 BH4 inhibitors can overcome acquired radioresistance in vitro and in vivo.
Compounds have been shown to have anti-tumor activity in lung cancer animal models.