Discovery of CDK8/19 inhibitors as lead compounds for IL-6-dependent lymphoma enabled by the formal synthesis of cortistatin A.

Authors

Wenjun Wang, Nan Zhang, Baicheng Chen, Zijing Chen, Guihua Zeng, Tuoping Luo

Published in

Science advances. Volume 12. Issue 36. Pages eaeg8852. Sep 04, 2026. Epub Sep 04, 2026.

Abstract

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.

PMID:
42696577
Bibliographic data and abstract were imported from PubMed on 05 Sep 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.