Cancer is a deadly disease affecting millions of people worldwide. Irreversible inhibitors are making a strong comeback in cancer therapeutics as evident by recent approval of covalent drugs. Inhibiting kinases/ pathways that are either overexpressed or constitutively active in cancer patients and have surface exposed cysteine are ideal candidates for the identification of covalent inhibitors. Nuclear factor kappa B (NF-κB) is a transcription factor that plays a key role in innate and adaptive immune responses, inflammation, cell growth, and apoptosis. The key proteins in this pathway, inhibitor of nuclear factor κB kinase β (IKKβ) and NF-κB, have surface exposed cysteine that plays an important role in its translocation to the nucleus to activate gene expression. Parthenolide, a sesquiterpene lactone natural product, displayed anticancer effects in cervical, breast, lung and pancreatic cancers, by inhibiting NF-κB pathway. Mechanism studies using click chemistry demonstrated that the sulfhydryl groups on Cys179 of IKKβ and Cys38 of NF-κB covalently reacts with the α-methylene-γ-butyrolactone moiety of Parthenolide. However, properties such as poor water solubility, poor stability in physiological pH, and structural optimization due to complex structure limits its usage. To address these issues, we synthesized and screened a focused library of hybrid small molecules that features α-methylene-γ-butyrolactone moiety in a pathway specific NF-κB luciferase assay. This led to the identification of an isatin derived spirocyclic “hybrid pharmacophore” scaffold that is amenable to modification and inhibits the NF-κB pathway by irreversibly binding to IKKβ and NF-κB. Structure activity relationship (SAR) studies revealed that rigidification of the α-methylene-γ-butyrolactone and the Michael acceptor in the spirocyclic system are two critical features required to improved biological activity. Lead compound inhibit cancer cell growth in vitro and tumor growth in an orthotopic ovarian cancer model. Overall, studies suggested that isatin-derived spirocyclic α-methylene-γ-butyrolactone mimics parthenolide activity and is suitable for further optimization to identify novel anticancer agents.<br/>

Isatin derived spirocyclic analogs with α-methylene-γ-butyrolactone as anticancer agents: A structure activity relationship study

251st National Meeting (2016)

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