BCL-2 (B-cell Lymphoma 2) is a protein that regulates cell death via anti-apoptotic or pro-apoptotic activity. It has two isoforms, with the name of 1G5M (isform 1) and 1G5O/1GJH (isoform 2). The protein exists in the outer membrane of mitochondria to promote cellular survival and suppress the pro-apoptotic proteins. BCL-2 also regulates mitochondrial dynamics, such as mitochondrial fusion and fission.

However, BCL-2 damage always causes various kinds of cancer diseases, such as prostate, melanoma, chronic lymphocytic leukemia and breast cancer. What’s more, it also induces resistance to cancer treatments. BCL-2 has become a target in the research of cancer. Thus, potent and selective BCL-2 inhibitors play a vital important role in cancer therapy.

In recent years, researchers have discovered hundreds of BCL-2 inhibitors. Some are selective, and some are non-selective. Patrick Casara, et al developed S55746 as a selective BCL-2 inhibitor. Now, let’s see how it works.

S55746 potently inhibits BCL-2, with a K_i of 1.3 nM. It exhibits ~70 to 400 fold selectivity over BCL-XL.

In cellular assay, S55746 selectively cause acute lymphoblastic leukemia cell death. It induces apoptosis by inhibiting BCL-2, and such inhibition is BAX/BAK-dependent.

In addition, S55746 suppresses tumor growth in vivo. In mice bearing RS4;11 cells, S55746 (25 and 100 mg/kg) significantly increases caspase-3 activity via oral administration. Besides, S55746 (200 and 300 mg/kg) dramatically inhibits tumor growth via oral route five times a week for 3 weeks.

S55746 is a potent, selective and orally active BCL-2 inhibitor. We’d better take full use of the compound in cancer treatment.