主催: The Japanese Pharmacological Society, The Japanese Society of Clinical Pharmacology
会議名: WCP2018 (18th World Congress of Basic and Clinical Pharmacology)
開催地: Kyoto
開催日: 2018/07/01 - 2018/07/06
Nuclear factor kappa B pathway is a major transcription factor cascade linked to a number of disease states. The cascade is regulated by isoforms of the inhibitory kappa B kinase (IKK) complex. IKKalpha regulates canonical signalling whilst IKKbeta regulates the non-canonical pathway via p100 phosphorylation and degradation, formation of p52 and p52/RelB mediated transcription. Considerable effort has been conducted to identify selective inhibitors of IKK isoforms, but with limited success. We have recently identified first-in-class compounds which selectively blocks non-canonical IKKalpha signalling (Anthony et al., 2017). Here we further show the utility of a more potent selective inhibitor which can also prevent functional responses.
U2OS and PANC-1 cell lines were utilised. Compounds were assessed for selectivity using an in vitro kinase assay. Intermediates of both pathways were assessed by Western blotting. Proliferation and cell cycle parameters where assayed as outlined previously (Lawan et al., 2011).
Both cell types responded to Lymphotoxin with an increase in p100 phosphorylation and enhanced p52 formation which was maximal by 4hr. In the case of U2OS TNFalpha; also mediated a unique early increase pp100/p52 which was maximal by 30 min. SU1261 was identified as an IKKalpha selective compound (Ki value (nM); IKKalpha 42, IKKbeta 1200, n=3); pre-treatment of cells cause a concentration-dependent inhibition of p100/p52 phosphorylation over the high nanomolar range with a similar reduction in p52 formation. However, SU1261 was without effect upon cellular IkappB alpha; loss or p65 phosphorylation, two markers of IKKbeta; activation. Pre-treatment with SU1261 also reduced proliferation, cell cycle progression, clonogenic survival and increased apoptosis. Furthermore, expression of CXCL12 was significantly reduced.
Taken together these studies confirm identification of first-in-class IKKalpha inhibitors which have the potential to reduce cellular proliferation per se or the induction of mediators which can support tumour survival.
References.
1)Anthony NG, Baiget J, Berretta G, Boyd M, Breen D, Edwards J, et al. (2017). J Med Chem 60: 7043-7066.
2)Lawan A, Al-Harthi S, Cadalbert L, McCluskey AG, Shweash M, Grassia G, et al. (2011). J Biol Chem 286: 12933-12943.
