The noncanonical NF-κB pathway regulates the transcription of the protein APOBEC3B (A3B), whose overexpression has been linked to cancerous behavior in cells and has been found in over 50% of breast cancer tumors. As such, inhibition of the proteins on the noncanonical pathway would diminish overexpression of A3B and prevent tumor evolution. Our goal is to develop selective inhibitors for two kinases on this pathway, inhibitor of IκB kinase 1 (IKK1) and NF-κB inducing kinase (NIK). Beginning with atomic-resolution crystal structures of our target proteins, we have used molecular dynamics (MD) to elucidate the behavior of these ligand-protein systems and virtual screening to identify leads for small molecule inhibitors. First, we have begun designing an inhibitor of IKK1. Provided with a novel crystal structure of the IKK1 complex, we were able to find druggable hotspots. Through cycles of virtual screening and biochemical assays with our collaborators, we have identified hits from a compound virtual library. From there, we have screened analogs and derivatives of the first round of actives to identify further hits. By focusing on a binding pocket away from the active site and expanding our field of potential actives, we aim to design an inhibitor that will be specific to IKK1.<br/> <br/>Second, taking protein-ligand co-crystal structures, we have used MD to model the dynamics of NIK bound to existing but currently unpursued drugs. Analyzing our MD simulations, we have dissected the behavior of the NIK active site by looking at interactions of crucial residues, quantifying changes loop dynamics, and identifying cryptic side pockets. We have also identified a possible allosteric site, and demonstrated that the allosteric site-binding ligand induces similar behavior in NIK to that of the active site-binding ligand. We will use our novel models to improve on the selectivity and potency of NIK inhibitors.

Anti-cancer drug discovery efforts target two kinases on the non-canonical NF-κB pathway

253rd National Meeting (2017)

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