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Scientific Background
Caspase induction controls apoptosis in cells
The primary goal of almost all cancer drugs is to selectively induce apoptosis, or programmed cell death, in cancer cells. There are many different pathways that lead to apoptosis, all of which converge to activate a family of cysteine-aspartyl proteases called caspases. There are 12 caspase enzymes in humans, divided into three classes:
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Inflammatory (caspases-1, -4, and ‑5)
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Apoptotic initiator (caspases-2, -8, -9, -10, and -14)
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Apoptotic executioner (caspases-3, -6, and -7)
Apoptosis is induced in cells when the inactive, or pro-forms, of apoptotic initator caspases are activated. Apoptotic initiator caspases, in turn, activate executioner caspases. In the final step of apoptosis, the activated executioner caspases kill the cell by selectively cleaving more than 1,000 proteins.
Caspases are synthesized as inactive pro-enzymes that require proteolytic activation
Caspases are synthesized as inactive pro-enzymes containing a prodomain, a small subunit, and a large subunit. Procaspases require cleavage between their large and small subunits for conversion to the active, mature form of the enzyme. The initiator caspases require recruitment to larger complexes to induce procaspase dimerization and auto-proteolytic activation. The executioner procaspases, which exist as preformed inactive dimers, are cleaved and activated by the initiator caspases, caspase-8 and -9.
Small molecules can activate caspases by binding at allosteric sites on the pro-enzyme
Procaspases and caspases are highly dynamic enzymes that can exist in at least two different states: an on-state and an off-state. The mature form of the executioner caspases exists primarily in the on-state, and active site inhibitors can trap the enzyme in this state. The corresponding proenzymes exist primarily in the off-state. Caspase activators that bind at allosteric sites on the proenzyme were identified by screening for small molecules that stabilized the on-state of one or more executioner procaspases long enough to allow autoactivation and proteolytic cleavage (Wolan Science: 326: 853, 2009).
Caspase activators can work downstream of chemoresistant blockades in cancer cells
A majority of the conventional chemotherapeutic agents used to treat cancer cause DNA damage or cell cycle arrest, thereby inducing p53 stress pathways and caspase activation. But many cancer cells delete or mutate p53, blocking the ability of the cell to sense upstream distress signals. Chemoresistance can also be promoted in cancer cells by increased expression of anti-apoptotic bcl-2 proteins that block induction of the apoptosis pathway. By acting downstream of these blockades, activators of caspase-9 and the executioner caspases have the potential to induce apoptosis in these chemoresistant tumors. Another key anti-apoptotic pathway is one that is mediated by the IAP proteins (XIAP, survivin, etc). IAPs, which are upregulated in many tumors, inhibit the activated form of executioner caspases by acting as ubiquitin ligases and promoting rapid caspase degradation by the proteasome. Caspase activators have the potential to perturb the balance in the rate of caspase activation and caspase turnover in these cells, tipping the cells toward apoptosis.
Caspase expression is increased in some cancers
Caspases are not commonly deleted or inactivated in tumors, but expression of caspases can vary. In the NCI-60 collection of tumor cells, expression of caspases -9, -8 , and -3 was found to be particularly variable (Svingen Clin Cancer Res: 10 6827 2004). For several tumor types, incuding breast, lung, and colon cancer, specific caspases have been shown to be upregulated relative to their surrounding normal tissue. In addition, hematological tumors express high levels of multiple caspases. These tumor types with elevated caspase expression may have greater sensitivity to caspase activators.
Caspase activators have the potential to be powerful anti-cancer agents, either alone or in combination with conventional chemotherapeutics, in a wide variety of solid tumors and heme malignancies, even in chemoresistant, late-stage cancers.
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