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Pfizer taps Effector Therapeutics for its anticancer translation inhibitor

Effector’s eIF4E inhibitor is designed to halt the output of cancer-driving mutations in the PI3K pathway

by Ryan Cross
January 13, 2020 | APPEARED IN VOLUME 98, ISSUE 2

 

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Credit: Effector Therapeutics
A scientist at Effector Therapeutics in San Diego

Pfizer is striking a deal with Effector Therapeutics, a San Diego–based startup that’s developing small-molecule drugs to inhibit hyperactive translation in tumors.

The big pharma firm will pay Effector $15 million upfront to license a preclinical inhibitor of a protein called eukaryotic initiation factor 4E (eIF4E). Effector stands to earn up to $492 million more in R&D funding, as well as development and sales milestones.

Effector was founded in 2012 based on translation research by Davide Ruggero and Kevan Shokat at the University of California, San Francisco. Its CEO, Steve Worland, trained as a chemist and, prior to joining Effector in 2012, was CEO of Anadys Pharmaceuticals. Before that, he headed antiviral research at Pfizer.

The biotech firm has three drug programs, all focused on blocking proteins that control translation, the process that cells use to read a messenger RNA code to make proteins.

The programs all target what Worland dubs an effector protein. These effector proteins receive signals from kinases and other signaling proteins frequently implicated in cancer, such as KRAS and PI3K. The effector protein acts as a final lever cranking up the translation of mRNAs that help cancer cells survive, proliferate, and evade detection by the immune system.

The goal is to stop cells whose translation of these mRNAs is in overdrive, while leaving normal levels of translation in healthy cells unaffected. “It’s like we are taking the turbocharger off the engine, but the engine is still running just fine,” Worland says.

eIF4E, an effector protein, is sometimes found at high levels in cancer cells. That provides one impetus to target it, but Worland says the biggest reason drugmakers are excited about eIF4E inhibitors is that the protein is the final step in a cellular pathway that includes PI3K. The so-called PI3K-AKT-mTOR pathway is frequently mutated in cancer, throwing translation dependent on eIF4E into overdrive. Many drugs designed to block the pathway have failed.

“eIF4E has been known in the industry as an attractive target, but written off as an undoable target,” Worland says. eIF4E’s natural binding partner, or ligand, is highly charged and derived from guanosine, two factors that give it poor permeability. A synthetic version of the ligand would have trouble easily entering cells.

“Most things that would bind to this site don’t look anything like drugs,” Worland adds. Although his firm hasn’t published any details about its eIF4E inhibitor, it’s clear that Pfizer liked what it saw.

Although a few PI3K inhibitors are on the market, cancer cells are known to develop resistance to these drugs by rewiring their signaling circuitry to become less reliant on PI3K. eIF4E operates outside the feedback loops that enable resistance to PI3K, Worland says.

Effector is also developing an inhibitor for another effector protein, eIF4A, which turns on different genes and is activated by different signals than eIF4E. eIF4A is turned on by a pathway that includes KRAS, a protein that is mutated in many difficult-to-treat cancers. KRAS has been devilishly difficult to drug, and no approved inhibitors exist, although many companies are now making headway. The eIF4A inhibitor, called zotatifin, is now in a Phase I clinical trial.

Pfizer first partnered with Effector in 2017 to test another of the start-up’s compounds, a small-molecule inhibitor of MNK1 and MNK2 proteins, in combination with avelumab, a checkpoint inhibitor from Pfizer and Merck KGaA. That MNK1/2 inhibitor, now called tomivosertib, stops the translation of mRNAs involved in cancer proliferation and immune evasion. It is now in a Phase II clinical trial.

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