Targeting STAT3 and STAT5 in Cancer

Dear Colleagues,

Cancer is driven by hyperactivation of the JAK–STAT core cancer pathways associated with inappropriate functions of normal signaling pathways involving cytokine, growth factor and hormone action. The successful implementation of clinically approved JAK kinase inhibitors (baracitinib, ruxolitinib and tofacitinib) is proof that JAK–STAT targeting is beneficial. Consequently, targeting oncogenic transcription factors of the STAT family, namely STAT3, STAT5A and STAT5B as major funnels for gene regulatory processes including chromatin remodeling facilitated by them has therapeutic power. STAT3/5 proteins are attractive targets for drug discovery since they steer proliferation, survival and metabolism. Targeting protein-protein interactions, however, is challenging since the interacting surfaces are typically large and flat, having non-contiguous binding hot spots and lack of deep tractible pockets. Furthermore, targeting transcription factors is considered “undruggable”. Emerging drug design strategies and medicinal chemistry approaches, including methods to impair function, to destabilize or degrade transcription factors or to interfere with interaction partners and cofactors, initiated new concepts. Here, we summarize targeting approaches on STAT3/5, where the field moves into clinical application. We cover the design paradigms and medicinal chemistry approaches to illuminate limitations in specificity, potency, and in vivo bioavailability, necessitating approaches.

Focus of this Special Issue:

STAT3/5 activation is at the convergence point of many signaling pathways, activated by a plethora of upstream kinases and STAT3- and STAT5-targeting approaches in cancer is up for article invitation for this Special Issue.

Prof. Dr. Richard Moriggl
Prof. Dr. Patrick Gunning
Prof. Dr. György Miklós Keserü
Guest Editors

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