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Gilead buys Nimbus’s NASH portfolio

$400 million deal adds ACC inhibitors to Gilead’s liver disease pipeline

by Lisa M. Jarvis
April 5, 2016 | APPEARED IN VOLUME 94, ISSUE 15

In a bid to strengthen its liver disease drug pipeline, Gilead Sciences will pay $400 million up front for Nimbus Therapeutics’ small molecules for nonalcoholic steatohepatitis (NASH), a liver disease that can lead to cirrhosis.

Currently, no drugs exist to treat NASH, which begins with fat deposits in the liver and can cause scar tissue to accumulate. Up to 5% of Americans have NASH and another 10–20% have fat in their liver, according to the National Institutes of Health.

Structure of soraphenA.
Credit: Nimbus
Credit: Nimbus

With the deal, Gilead gets Nimbus’s allosteric inhibitors of acetyl-CoA carboxylase (ACC), an enzyme critical in fatty acid synthesis. Other companies—most recently Pfizer—have tried to develop drugs that block the activity of ACC, but their compounds have not been potent enough.

Those earlier molecules were intended to block the enzyme’s active site, a shallow, hydrophobic pocket that is a chemist’s “worst nightmare,” says Nimbus CEO Don Nicholson.

Nimbus took a different tack. The natural product Soraphen A was known to slow the growth of yeast by nestling into an allosteric site on the enzyme. Working with its computational chemistry partner Schrödinger, Nimbus designed molecules that had the properties and interactions of the unwieldy natural product “but with the structure of a proper drug,” Nicholson says.

Earlier molecules were intended to block the enzyme’s active site, a shallow, hydrophobic pocket that is a chemist’s “worst nightmare.”

The virtual ACC inhibitors were then synthesized and improved upon by Nimbus chemists. Within 18 months, the biotech firm had an allosteric ACC inhibitor ready to be put into human studies.

Gilead is getting Nimbus’s lead drug candidate NDI-010976, which is poised to enter Phase II studies, and a series of follow-on compounds.

Gilead’s NASH portfolio already includes two treatments in Phase II studies—the LOXL2 inhibitor simtuzumab and the ASK1 inhibitor GS-4997—and an FXR agonist in Phase I that came through its acquisition of Phenex Pharmaceuticals.



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Curious Wavefunction (April 6, 2016 1:19 PM)
I do hope Nimbus decides to publish at least some of the computational protocols which they used to discover this inhibitor. That would allow the community to get some insights into the domain of applicability of these protocols. Some useful questions that Nimbus can answer:

1. Did they have a crystal structure or did they build a homology model? If they built a model, what was the sequence identity.
2. Was the protein flexible or was it fairly rigid? Were there missing loops or other parts and did they use Prime for building these loops? If loops were actually reconstructed, what was their length?
3. What was the success rate of their virtual screening campaign? How many top ranked molecules were actually made?
4. How much did Schrodinger's WaterMap protocol help with improving binding affinity? Were the key water molecules buried deep in hydrophobic cavities or were there also a few non-intuitive water molecules at the protein-solvent interface?
5. Did they test any of the false negatives to know if the accuracy was what they thought it was?
6. How well did the new FEP algorithm work in terms of rank ordering binding affinity? Did they compare this method with other simpler methods like MMGBSA?
7. In what way, if at all, did molecular dynamics help in the discovery of these inhibitors? How did MD compare to simpler techniques?

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