Discovery of CDK8/19 Inhibitors As Lead Compounds for IL-6-dependent Lymphoma Enabled by the Formal Synthesis of Cortistatin A.

A formal synthesis of cortistatin A, a marine-derived steroidal alkaloid with potent anti-angiogenic and antileukemic activities, was achieved via a unique synthetic strategy that leveraged a late-stage SmI2-mediated oxa-bridge translocation. The de novo-synthesized simplified analog CA411 was evaluated across 38 cell lines, revealing potent and selective antiproliferative activity against a diffuse large B cell lymphoma (DLBCL) line OCI-Ly3. Time-course transcriptomics and mechanistic studies demonstrated that it disrupts an autocrine IL-6-JAK2-STAT3 signaling loop, reducing IL-6 secretion, STAT3 phosphorylation, and downstream anti-apoptotic genes, thereby inducing apoptosis. Not only this selectivity extends to other CDK8/19 inhibitors and IL-6-dependent models, but CA411 also suppressed OCI-Ly3 xenograft growth, diminished IL-6 expression, induced anti-angiogenic effects with vascular normalization, and prolonged survival in mouse models. These findings position CDK8/19 inhibitors like cortistatins as leads for IL-6-dependent lymphomas, highlighting a targetable vulnerability in cytokine-driven malignancies and bridging synthetic innovation with therapeutic discovery.