NIFT- First in class NEDD4 Inhibitors For cancer Therapy

NEDD4, an E3 ubiquitin ligase enzyme from the HECT family, selectively targets specific substrates for ubiquitination, and its upregulation has been observed in several cancers, making NEDD4 inhibitors a promising novel approach for cancer therapy. 

IFOM researchers discovered, through structure-based design, novel tricyclic compounds that inhibit NEDD4 ubiquitin E3 ligase enzyme with high potency (nM range) by binding the allosteric "Ub exosite" and blocking polyubiquitination, with high affinity and selectivity for NEDD4 over other family members (like NEDD4-L, ITCH, and HECW2), while preserving part of physiological function of NEDD4.

We identified a lead compound with favourable ADME properties, good pharmacokinetic (PK) profile and in vivo proof of concept with good tollerability.