IL-6 has emerged as a potential target for the development of antitumor agents. IL-6 acts as a growth factor or antiapoptotic factor in various malignancies, including multiple myeloma, mesothelioma, and renal cell carcinoma and numerous other cancers. IL-6/GP130 homodimerization triggers the JAK2/STAT3 signaling cascade via interaction with the extracellular domain of IL-6R and GP130, resulting in homodimerization of the heterotrimeric IL-6/IL-6R/GP130 complex. Thus, this complex plays a key role in tumor development in IL-6 dependent cancer cells, the interaction of the IL-6 with GP130 may be a therapeutic target in these IL-6-related diseases. Madindoline A, a natural product isolated from the fermentation broth of Streptomyces nitrosporeus K93-0711 is reported as an antagonist to homodimerization of GP130 in IL-6 dependent cancer cells.  The existing synthetic routes to madindoline A show limited applicability in drug discovery efforts and moreover the extraction from its natural source is no longer possible due to mutation in the bacterial strain. Our efforts focus both on simplification of the madindoline A structure and incorporation of functional groups predicted to provide additional binding interactions with the receptor in order to increase synthetic feasibility and develop potent synthetic analogues. MDL-16 has been identified and validated as a potent IL-6 antagonist with significant in vitro antitumor potency based on the natural product Madindoline A. In the current study, further modification of MDL-16 has led to a new class of analogues inhibiting the IL-6/JAK/STAT pathway. Furthermore, SAR optimization of these compounds and exploration of SAR is ongoing to develop novel and potent IL-6/GP130 inhibitors.

Madindoline A as a lead for the development of new class of IL-6/GP130 homodimerization inhibitors

246th National Meeting (2013)

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