Pfizer taps Effector to develop anti-cancer eIF4E inhibitors

Pfizer has teamed up with Effector Therapeutics to develop small molecule inhibitors of eukaryotic initiation factor 4E (eIF4E). Effector is set to receive $15 million upfront to work on drugs against the oncogenic driver, which is found downstream of the RAS and PI3K signaling pathways.

Interest in the oncogene eIF4E dates back decades. Eli Lilly worked with Ionis Pharmaceuticals, then known as Isis, to take an eIF4E antisense drug into the clinic in 2006. Other groups ran preclinical tests showing molecules such as hippuristanol, pateamine A and silvestrol act on other parts of the eIF4F complex, which includes the cap-binding protein eIF4E. 

Yet eIF4E has proven to be a tough target, preventing the industry from using knowledge of its role in resistance and poor cancer outcomes to develop new, more effective therapies.

Working with Pfizer, Effector wants to change that. The partners will collaborate on the development of small molecules that inhibit the effector protein, thereby countering the activation that is thought to drive certain cancers.

Pfizer is paying $15 million upfront to enter into the collaboration, which gives it a global license to the resulting eIF4E inhibitors. Effector is also in line to receive up to $492 million in R&D funding, development and sales milestones. If an inhibitor comes to market, Effector will pocket royalties, and, if it opts in, a split of any profits and losses made in the U.S.

Effector framed the deal as a justification for its decision to work on eIF4E despite the challenging nature of the target. 

“We believe that this agreement validates Effector’s pursuit of eIF4E, which has been a protein of interest for drug development for many years but has been very challenging to develop small molecules to target due to the nature of its binding site,” Effector CEO Steve Worland said in a statement.

Effector’s work on eIF4 to date has yielded zotatifin, an inhibitor of the eIF4A component of the complex that began phase 1/2 testing in patients with solid tumors late last year. The early-phase trial is enrolling people with any KRAS mutation subtype or activating mutations, amplifications or fusions in HER2, ERBB3, FGFR1 or FGFR2 receptor tyrosine kinases. Effector also lists inhibitors of eIF4A in its early phase pipeline and will now take that program forward with Pfizer.