Design and synthesis of inhibitors of the non-canonical NF-ĸB pathway for the treatment of prostate and pancreatic cancer

Previously held under moratorium from 12th March 2018 until 7th June 2023.The dysregulation of the transcription factor NF-κB has been linked with multiple pathologies including cancers, inflammatory diseases and autoimmune conditions. Under basal conditions, NF-κB is held in an inactive state in the cytosol. Upon stimulation, in response to cellular stress, NF-κB translocates to the nucleus where it is able to activate gene expression. These genes include a number of pro-inflammatory cytokines, growth factors and pro-survival genes. Targeting specifically the non-canonical NF-κB pathway with small molecule inhibitors has been suggested as a possible therapeutic intervention for prostate and pancreatic cancers. The non-canonical NF-κB pathway is highly dependent on the enzyme NF-κB-inducing kinase (NIK). This kinase is responsible for the phosphorylation of the downstream kinase IKKα which, in turn, phosphorylates the p100 protein. Proteolytic processing of p100 releases the NF-κB subunit p52 which dimerises with RelB to form the NF-κB protein complex. This project involves the design and synthesis of small molecule inhibitors of IKKα and NIK as potential prostate and pancreatic anti-cancer compounds. A series of amidopyridines were shown to be selective inhibitors of IKKα over the related isoform IKKβ and an SAR study identified some compounds with single digit nanomolar potency against IKKα and some with greater than 500-fold selectivity for IKKα over IKKβ. Development of NIK inhibitors showed substituting the 4-position of a pyrrolopyrimidine scaffold with a 6- substituted indoline provided sub-micromolar potency against NIK. SAR was carried out on both ring systems leading to synthesis of a known NIK inhibitor which was shown to have potent cellular activity and tractable pharmacokinetic properties but poor selectivity over a wider panel of kinases. Further development led to a compound which retained good potency against NIK but with a far superior off-target profile compared to the known NIK inhibitor.The dysregulation of the transcription factor NF-κB has been linked with multiple pathologies including cancers, inflammatory diseases and autoimmune conditions. Under basal conditions, NF-κB is held in an inactive state in the cytosol. Upon stimulation, in response to cellular stress, NF-κB translocates to the nucleus where it is able to activate gene expression. These genes include a number of pro-inflammatory cytokines, growth factors and pro-survival genes. Targeting specifically the non-canonical NF-κB pathway with small molecule inhibitors has been suggested as a possible therapeutic intervention for prostate and pancreatic cancers. The non-canonical NF-κB pathway is highly dependent on the enzyme NF-κB-inducing kinase (NIK). This kinase is responsible for the phosphorylation of the downstream kinase IKKα which, in turn, phosphorylates the p100 protein. Proteolytic processing of p100 releases the NF-κB subunit p52 which dimerises with RelB to form the NF-κB protein complex. This project involves the design and synthesis of small molecule inhibitors of IKKα and NIK as potential prostate and pancreatic anti-cancer compounds. A series of amidopyridines were shown to be selective inhibitors of IKKα over the related isoform IKKβ and an SAR study identified some compounds with single digit nanomolar potency against IKKα and some with greater than 500-fold selectivity for IKKα over IKKβ. Development of NIK inhibitors showed substituting the 4-position of a pyrrolopyrimidine scaffold with a 6- substituted indoline provided sub-micromolar potency against NIK. SAR was carried out on both ring systems leading to synthesis of a known NIK inhibitor which was shown to have potent cellular activity and tractable pharmacokinetic properties but poor selectivity over a wider panel of kinases. Further development led to a compound which retained good potency against NIK but with a far superior off-target profile compared to the known NIK inhibitor