‘Irreversible’ drug toxic to ovarian cancer

USC (US) — A new type of drug for ovarian cancer latches on and doesn’t let go—which means patients could take fewer doses, and that it may be effective for drug-resistant cancers.

The drug is a member of a new class of cytotoxic agents abbreviated as PACMA that was discovered by testing roughly 10,000 chemical compounds on cancer cells in the lab of Nouri Neamati, professor of pharmacology and pharmaceutical sciences at the University of Southern California (USC) School of Pharmacy.

“We need a new generation of drugs. We need to overcome the drug-resistance issue,” says graduate student Shili Xu, the lead author of the paper published in Proceedings of the National Academy of Sciences.

In order to investigate and optimize the anticancer properties of PACMAs, researchers synthesized over 80 newly designed compounds—one called PACMA31 was eventually found to be extremely toxic to ovarian cancer cells and a potentially highly effective drug.


PACMA31 is a potent and selective inhibitor of a protein called Protein Disulfide Isomerase (PDI) that is highly expressed in ovarian cancer, can be taken orally, and accumulates in cancer cells, which means that it is less likely to cause harmful side effects in normal tissues.

It also is what is known as an “irreversible” drug, meaning that it latches on to its target, PDI, permanently and refuses to wear off until the protein is degraded.

That irreversibility may result in prolonged duration of drug action that could translate into giving the patients lower doses of drugs. “We are exploring combination studies in order to find synergy between our drug and first-line therapy for ovarian cancer,” says Neamati.

Currently, there are two major types of drugs in the first-line treatment of ovarian cancer: paclitaxel, which hinders cancer cell division by inhibiting the disassembly of microtubules; and carboplatin, which binds to and causes crosslinking of DNA that results in cancer cell death.

PACMA31 attacks cancer cells in yet a different way, targeting PDI and thus interrupting the folding process during which proteins assume the shapes that allow them to function properly. Accumulation of misfolded proteins in a cell causes cellular stress and eventually cancer cell death.

Because PACMA31’s strategy is different than that of current anticancer drugs, it has the potential to help patients who do not respond to paclitaxel or cisplatin.  “When the patient has no other choice, we could potentially treat them with our drug,” Neamati says.

The drug has only been tested in the lab on ovarian cancer cells and on mice with tumors and will require additional testing, but so far appears to be nontoxic and effective at halting tumor growth. It may also have potential for treating other types of cancer, Neamati says.”Obviously, we think that it will go beyond ovarian cancer.”

Funding for the research came from the USC Zumberge Research and Innovation Fund, the American Chemical Society, the William Cockrell Endowed Cancer Research Fund, and the Department of Defense Ovarian Cancer Program.

Source: USC