The developmental and inflammatory disease target protein ADAM17 is vulnerable to off-target interaction by the drug...

The loss of proteolytic activity of ADAM17 causes birth defects and embryonic lethality. Conversely, inhibiting ADAM17 activity represents a potential strategy for treating inflammatory and autoimmune diseases. ADAM17 has an active site cleft with a divalent Zn ion and hydrophobic S1'/S3' subsites interconnected to form an L shaped cavity. However, it is currently unknown whether the active site of ADAM17 is susceptible to off-target inhibition by the small molecule drug eltrombopag, which contains metal-binding moieties and is classified as pregnancy category C by the FDA. The in-depth molecular modeling analysis in this study revealed that the unique structural features of L-shaped S1'/S3', crucial for determining ADAM17 specificity, along with spatial constraints imposed by active site amino acid residues, create an ideal binding environment for eltrombopag. Interestingly, the structural peculiarity of L-shaped S1'/S3' cavity enabled the carboxylate group rather than the traditionally recognized metal binding domain of eltrombopag to chelate catalytic Zn of ADAM17. Further, eltrombopag's biphenyl and xylene groups embed in the S1'/S3' subsites and pyrazole and hydrazine linker occupy the interconnecting tunnel, forming a stable eltrombopag-ADAM17 complex. These novel findings from molecular modeling suggest that ADAM17 is an off-target of eltrombopag, a drug used to increase platelet production in thrombocytopenia. They stimulate further in vitro and in vivo studies to test the repurposing potential of eltrombopag as an ADAM17 inhibitor to prevent tissue destruction in autoimmune diseases in adults and whether the use of eltrombopag during pregnancy could potentially lead to developmental toxicity due to ADAM17 inhibition.