An interdisciplinary team of Boston University (BU) professors is launching a project to develop new ways to target protein-protein interactions (PPIs) with synthetic organic drugs. Financed by a four-year $1.6 million grant from the NIH, the goal is to develop new approaches for discovering drug-like small molecule inhibitors against challenging protein-protein interaction interfaces.
The work will determine if appropriately designed synthetic macrocycles can inhibit PPI targets while maintaining good drug-like properties. The test system is the intracellular PPI target NFB essential modulator (NEMO), a component of κB kinase (IKK) complex inhibitor. Chronic hyperactivity of the NFκB pathway is found in human inflammatory diseases and cancers. Inhibiting the interaction of NEMO with IKKβ, as a more targeted alternative to completely ablating all IKK kinase activity, represents a promising new approach for attenuating inflammation, the researchers believe.
Only about 10% of the potential drug targets in the human genome have been successfully targeted with marketed drugs, according to the BU group. Of the remaining 90%, a large proportion are intracellular proteins whose function is critically dependent on their reversible interactions with other proteins, they add.
Led by College of Arts & Sciences professor of quantitative biochemistry and drug discovery Adrian Whitty, Ph.D., the research team includes professors Sandor Vajda, Ph.D., and Dima Kozakov, Ph.D. (computational chemistry), John Porco, Ph.D., and Aaron Beeler (macrocycle design and synthesis), Ph.D., Karen Allen (x-ray crystallography), Ph.D., and Tom Gilmore, Ph.D. (NF-κB pathway biology).