Developing small molecule inhibitors for modulating cytokine IL18 activities

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Interleukin 18 (IL18), a member of interleukin-1 superfamily, is a critical effector molecule of inflammasome activation. IL18 signaling is initiated by its binding to the IL18 receptor (IL18R) a subunit, followed by the recruitment of the receptor b subunit to form a ternary complex. A naturally occurring antagonist of IL18, IL18 binding protein (IL18BP), prevents IL18 from binding to IL18R, potently inhibiting IL18 activity through a negative feedback mechanism. IL18 activities are important for immune responses to infection and tumors, but they are also involved in some inflammatory diseases. Thus, both up- and down-modulating IL-18 activities are pursued as therapeutic approaches for treating cancers or inflammatory diseases, respectively. The therapeutic potential of IL18 blockage for the treatment of adult-onset Still’s disease and auto-inflammatory hemophagocytic syndrome has been demonstrated by initial results from clinical trials with human IL18BP. On the other hand, IL18BP was recently found to be a major immunotherapeutic barrier for anti-tumor activity of IL18, and an engineered IL18 mutant capable of evading IL18BP inhibition showed greatly enhanced anti- tumor effects in mouse models1. The current therapeutic approaches that involve the modulation of IL18 activities are all protein-based. The ultimate goal of our proposal is to develop small molecules that can either up- or down-modulate IL18 activities, which can be used in cancer immunotherapy and for treating inflammatory diseases, respectively. We have made significant contributions towards structure-function of IL18 and IL18BP2,3. We revealed three pockets on IL18 surface that interact with IL18BPs and identified small molecules that either inhibit IL-18 activities or inhibit IL18BP binding with no deleterious effect on IL18 activities. We propose following structure-function studies of the small-molecule IL-18 modulators, which are essential for structure-guided design of small-molecule therapeutics. Aim 1. Structure-function studies on small molecule inhibitors of IL18. We have identified a small molecule that directly binds IL18 at a ‘hot spot’ on the surface and inhibits its bioactivities. We will carry out further mechanistic studies on the compound by biochemical and biophysical approaches. We will carry out larger scale virtual screening, functional assays and structural biology to identify additional compounds with different scaffolds. Aim 2. Structure-function studies on small molecule inhibitors of IL18BP function. We have identified two compounds that directly bind IL18 at different surface locations, blocking IL18BP binding however retaining IL18 receptor signaling. We will use similar approaches as in aim 1 to characterize these compounds and further identify additional ones as IL18BP inhibitors. Modulating IL18 signaling with small molecules is a novel and promising approach for treatment of inflammation and cancer immunotherapy. Successfully accomplishing the aims will not only provide a better understanding of IL18 biology, but also provide critical platform for future development of new therapeutics against a number of human diseases.