The Role of Caspases in Cancer
Conatus Pharmaceuticals' programs in oncology focus on the development of small molecule agents that stimulate the process of apoptosis, also known as programmed cell death. In cancer, the natural processes that lead to apoptosis are often blocked, preventing the removal of cancer cells and thus facilitating the growth of tumor tissue. Caspases are a family of enzymes known as cysteine aspartyl proteases that play a central role in process of apoptosis. Activation of these enzymes leads to fragmentation of DNA and ultimately the death and clearance of cancer cells.
Two main pathways exist that lead to caspase activation: the extrinsic pathway that relies on binding of activating ligands to specific extracellular receptors and the intrinsic pathway that becomes activated upon a variety of intracellular stress signals (see figure below). Activation of either the extrinsic or intrinsic pathways will ultimately converge into a final common pathway and trigger apoptosis.
Given the fundamental life and death function of these enzymes, it is critical that the modulation of caspase activity remain tightly controlled. Multiple regulatory feedback mechanisms effectively maintain an appropriate balance between activation and inhibition of caspase activity under normal physiological conditions. In the setting of cancer, however, critical control mechanisms are often hijacked to favor inhibiting the activity of caspases, therefore enabling cancer cells to survive and facilitating tumor growth.
Conatus Pharmaceuticals is targeting a family of proteins known as IAPs (Inhibitor of Apoptosis Proteins) which are known to block caspase activity, inhibit apoptosis and importantly to be associated with human cancers (refer to figure). Under normal conditions these proteins play a vital role acting as a "break" on unintended or excessive apoptosis that would result in tissue damage. Expression of these proteins is often increased in human cancers, preventing the removal of cancer cells and reducing the efficacy of cancer therapies. Three members of the IAP family, cIAP1, cIAP2 and XIAP, are the most significant regulators of caspase activity. Therefore, strategies to inhibit the action of IAPs and thereby facilitate caspase driven apoptosis represents a very attractive approach for the development of new cancer therapeutics.
Bcl-2 Inhibitors
This family of pro-survival proteins, which includes Bcl-2, Bcl-xL and Mcl-1, repress apoptosis and are commonly over-expressed in human cancers. Bcl-2 proteins are well documented to be associated with the maintenance and progression of tumors. Additionally, these proteins are closely associated with resistance to existing chemotherapies. Therefore, antagonizing the activity of Bcl-2 family members can have a direct impact on tumor progression, as well as improving the efficacy of established, clinically important chemotherapeutic regimens.
There are a number of drug candidates currently in clinical trials for this target. Abbott and Idun Pharmaceuticals participated in a novel drug discovery program to identify small molecule "fragments" that interfere with protein-protein interactions, specifically interactions with the BH3 binding groove of Bcl-xL (A in figure below). The BH3 binding domain is a large hydrophobic pocket and is the region where cognate proteins bind. Binding to this domain is a prerequisite for the pro-survival activity of all Bcl-2 family members. Extensive in vitro optimization, including detailed mechanism of action studies coupled with comprehensive characterization in animal models of cancer, led to the advanced development lead ABT-737 (B in figure below), and ultimately to the selection of a Bcl-2 inhibitor for clinical development. The selected clinical compound is currently under clinical evaluation in over a dozen Phase 1 and Phase 2 clinical trials, including various solid tumors and lymphoid cancers.
