and Patrick Harran with
a model of DZ-2384
Photo courtesy of
Reed Hutchinson/UCLA
A new compound holds promise for treating leukemia and other cancers, according to researchers.
The compound, DZ-2384, is a synthetic version of diazonamide A, a toxin isolated from a marine animal.
DZ-2384 is a microtubule-targeting agent (MTA). It binds to and alters the stability of microtubules, disrupting the normal function of the mitotic spindle and arresting cell-cycle progression at mitosis, ultimately leading to cell death.
However, researchers found that DZ-2384 behaves somewhat differently from other MTAs.
They reported these findings in Science Translational Medicine. The research was supported, in part, by Diazon Pharmaceuticals Inc.
The researchers tested DZ-2384 in mouse models of various cancers, including adult Philadelphia chromosome–negative acute lymphocytic leukemia.
In animals receiving DZ-2384, tumors shrank as much as or more than when a conventional MTA was used, but with much less toxicity at effective doses.
In particular, animals receiving DZ-2384 had markedly less peripheral neuropathy than those that received docetaxel, a conventional MTA. Peripheral neuropathy is one of the chief side effects of MTAs and can prompt treatment discontinuation.
“We have good reason to expect that human clinical trials of DZ-2384 will show that, at doses effective for treating a person’s cancer, there will be much less risk of the peripheral neuropathy that can force clinicians to stop treatment,” said study author Patrick Harran, PhD, of the University of California, Los Angeles.
Dr Harran believes clinical trials of DZ-2384 could begin within 2 years.
How this study began
Dr Harran began his work with diazonamides as a fundamental chemistry research problem.
In 1991, a group of researchers described diazonamides A and B, which they had isolated from the marine animal Diazona chinensis.
But Dr Harran and his colleagues found the described structure of diazonamide A was incorrect. In 2001, the team published a study that corrected the chemical structure of diazonamide A, and, 2 years later, they had synthesized the true structure in their lab.
Next, they began studying what the molecule might be doing to stop cells from dividing. In 2007, they discovered that the synthetic diazonamides they had produced minimized undesirable toxic effects that are commonly associated with chemotherapy.
Specifically, the compounds had an unusually large therapeutic window. In experiment after experiment, Dr Harran said, the researchers found that synthetic diazonamides’ therapeutic window was at least 10 times larger than that of traditional MTAs.
A key finding
In 2015, researchers prepared a form of DZ-2384 that was engineered with a molecular-scale “tracking device” so they could monitor its activity and better understand how it worked.
That helped the team confirm what they had come to suspect: that the compound binds to tubulin, which is a building block of mitotic spindles and a common target of MTAs.
Armed with this information, the researchers used X-ray crystallography to determine the structure of DZ-2384 bound to tubulin.
Their work offers a possible explanation for how DZ-2384 could disrupt dynamic tubulin polymers during cell division but spare those polymers in resting cells like neurons in the peripheral nervous system.
And that is what appears to allow the compound to attack growing cancer cells while minimizing damage to healthy cells.
