Hydroxyurea as a promising ADAM17 inhibitor

Abstract

A disintegrin and metalloproteinase-17 (ADAM17) is a multi-domain, type 1 trans-membrane protein with a zinc-binding catalytic domain and a rich history of research scrutinizing its cellular activation and presentation, shedding activity, and prominent physiological and pathological roles. Presently, despite the advancement in the inhibitory approaches focusing on ADAM17, clinically approved therapies targeting its inhibition are not available. A principal approach to inhibit ADAM17 involves ligating the catalytic zinc atom using a zinc binding group (ZBG), with the hydroxamate functionality being the principal ZBG directing the synthesis of a vast number of zinc-binders as ADAM17 inhibitors. In addition, multiple biological and pathophysiological pathways are involved in the activation and upregulation of ADAM17 with a capacity for pharmacological interventions to modulate these pathways and hence indirectly inhibit the activity of ADAM17. Thus, we hypothesize that hydroxyurea (HU), as the simplest hydroxamate, has the intrinsic ability to chelate the zinc atom of the active site region of ADAM17, which shares similarity with matrix metalloproteinases (MMPs) and carbonic anhydrases (CAs) as zinc-confining enzymes. Furthermore, our hypothetical argument sheds light on the structural characteristics, the nitric oxide (NO) donation properties, and the iron-chelating attributes of HU in addition to its immunomodulatory and anti-angiogenic activities; hence, a multi-faceted strategic targeting of ADAM17 is proposed that can be employed to put forward an approved hydroxamate-bearing compound as an inhibitor of ADAM17. Finally, a novel mechanism of action of HU is hypothesized that mandates further research within the field of therapeutics.