Inhibiting an enzyme that is important for fat synthesis led tumors to shrink in preclinical models of non-small-cell lung cancer, researchers reported in the Sept. 19, 2016, online issue of Nature Medicine.

As a consequence of tumor cells' tireless division, they are constantly in need of both energy and building blocks. One such building block is fatty acids, which are part of the cell membrane.

As a result, tumor cells don't just change their glucose and glutamine metabolism. They also need a lot of fat.

Where that fat comes from varies among tumor types. "Some tumors can take fat from the bloodstream," Rosana Kapeller told BioWorld Today.

But other tumors, including hepatocellular, ovarian, prostate and some types of breast tumors, are DIYers as far as fat is concerned – "totally dependent," Kapeller said, on making their own fats.

In such tumor types, inhibiting the enzymes that make fats is an obvious possible target. "People have known about ACC" – acetyl-CoA carboxylase, a critical enzyme in the synthesis of fatty acids – "for 20 years," Kapeller said, and "have been trying to drug it forever."

ACC, however, has proved to be a challenging adversary. The enzyme catalyzes a two-step reaction and has two active sites. One of those sites, the carboxyl transferase site, has been the subject of most attempts to drug ACC. But the site has several drawbacks. For one, because the active site is also the site where drug hopefuls would bind, "you are competing with substrate, which always makes it harder," Kapeller said.

Drugs that were strong enough to outcompete the substrate tended to run into toxicity problems, because multiple enzymes have carboxyl transferase sites, and so potent drugs tended to be nonspecific.

The net result was that a sweet spot between potency and toxicity has so far been elusive. "The majority of drugs never made it into phase II," Kapeller said.

Kapeller is the chief scientific officer of Nimbus Therapeutics Inc. and co-corresponding author of the paper now published in Nature Medicine. That paper describes the effects of ACC1 inhibitor ND-646 in non-small-cell lung cancer (NSCLC).

Keller, co-corresponding author Reuben Shaw from the Salk Institute, and their colleagues returned to ACC's second catalytic site, the biotin carboxylase site. Unlike the carboxyl transferase site, the biotin carboxylase site does have an inhibitor, the fungicide Soraphen A.

Soraphen A itself is too large, and too un-drug-like, to be even a lead. But the team recognized, Kapeller said, that "if we can mimic what Soraphen A does with some small molecule, that would be another step forward" for both cancer and non-alcoholic steatohepatitis (NASH), colloquially known as fatty liver, another disease in which cells overdo it on the fat synthesis.

Through computational chemistry approaches that were developed together with Schrodinger LLC, the team was "able to leverage the information that Soraphen provides to create a small molecule that had drug-like properties . . . that blocks ACC in the same way that AMP kinase does," Kapeller said. That molecule was ND-646.

In the work now published in Nature Medicine, the team showed that treating mouse models of NSCLC with ND-646, including KRAS-driven NSCLC, slowed tumor growth and had additive effects with carboplatin, the standard chemotherapy for NSCLC. KRAS is one of the most frequent cancer mutations overall, but attempts to drug it directly remain challenging despite recent progress.

The team also showed that in NSCLC, ACC1 was the main player whose inhibition affected tumor growth.

ACC exists in two forms, ACC1 and ACC2, and in fatty liver disease, it is important to inhibit both forms in order to prevent one from compensating for the other. In contrast, "in tumor cells, the key element is ACC1 in non-small-cell lung tumors," Kapeller said. "If ACC2 plays any role, it is a very small role, because you can't even detect ACC2 in these tumors."

In April, Gilead Sciences Inc. acquired Nimbus Apollo Inc., a subsidiary of Nimbus Therapeutics that owns the ACC assets. (See BioWorld Today, April 5, 2016.)

Gilead is in phase II trials with GS-0976 for the treatment of fatty liver disease. The company did not respond to a question about its plans, if any, for oncology indications of ACC inhibitors. But at the time of the acquisition, Jefferies LLC analyst Brian Abrahams wrote that the deal "exemplifies GILD's committed focus towards expanding in liver disease. (See BioWorld Today, April 5, 2016.)

Furthermore, hepatocellular carcinoma is one of the cancer types that need to make its own fatty acids, and ND-654, a cousin of ND-646, is in preclinical evaluation for that indication.