On June 22, 2020 Ikena Oncology, a clinical-stage biotechnology company that discovers and develops patient-directed, biomarker-driven therapies, reported the presentation of new preclinical research highlighting the anti-proliferative and anti-tumor effects of Ikena-developed compounds targeting the Hippo signaling pathway through the inhibition of TEAD at the 2020 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II, taking place June 22-24, 2020 (Press release, Ikena Oncology, JUN 22, 2020, View Source [SID1234561351]).
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The TEAD (TEA domain) family of transcription factors downstream of the Hippo signaling pathway elicits a gene expression signature that plays a prominent role in cancer development, progression, and metastasis. Increased Hippo pathway activity sustains proliferation, inhibits apoptosis, promotes angiogenesis, and is associated with resistance to multiple therapies. Inhibition of TEAD has been and remains an attractive opportunity for a novel targeted cancer therapy.
"The Hippo pathway is highly mutated across many cancer types, including in mesothelioma, ovarian and breast cancers, and its activation is correlated with an overall poor prognosis in patients. Therefore, we have insights into which patients will most likely benefit from a TEAD-targeted therapy," said Jeffrey Ecsedy, Ph.D., Chief Scientific Officer of Ikena Oncology. "The AACR (Free AACR Whitepaper) presentation this year highlights promising pharmacokinetic, pharmacodynamic, and in vivo efficacy results in mesothelioma models for multiple lead TEAD inhibitor candidates identified by Ikena. These compounds are in studies to narrow in on a development candidate that we look forward to progressing into IND-enabling studies during the second half of 2020."
Ikena’s Novel Small Molecule TEAD Inhibitors
Ikena researchers rationally designed and developed multiple novel, potent, orally bioavailable small molecule inhibitors that reversibly and irreversibly bind to the central lipid (palmitate) binding pocket of TEAD family members. These inhibitors prevent TEAD palmitoylation, a process that is essential for the interaction between the transcriptional co-regulators YAP (Yes-associated protein) or TAZ (transcriptional co-activator with PDZ-binding motif) with TEAD, and lead to downregulation of the YAP/TAZ-TEAD-dependent transcription. Binding of these TEAD inhibitors to the central lipid binding pocket was observed using crystallography.
The Effects of TEAD Inhibition In Vitro and In Vivo
When evaluated in vitro, Ikena’s TEAD inhibitors demonstrated anti-proliferative properties in Hippo pathway-driven cancer cell lines, but not in Hippo pathway wildtype cancer cell lines. Subsequent in vivo experiments in human tumor xenograft mouse models demonstrated that oral administration of these TEAD inhibitors was well tolerated and that TEAD-dependent transcription in the tumors was inhibited. Robust anti-tumor activity was observed in two separate Hippo pathway-mutated mesothelioma xenografts. Translational studies to identify additional tumor types that are Hippo pathway-driven and dependent on TEAD function are in progress.
"The Hippo pathway is hijacked in many cancer types and we believe that by disrupting TEAD transcription, we can prevent tumors from proliferating and evading the body’s immune system," said Mark Manfredi, Ph.D., President and Chief Executive Officer of Ikena Oncology. "We believe our TEAD inhibitor candidates have the potential to be active across several types of Hippo-driven cancers, both as single-agent therapy and in combination with other standard of care oncology agents to overcome therapeutic resistance."
Details for the AACR (Free AACR Whitepaper) 2020 Virtual Meeting II presentation are as follows:
Title: Potent small molecule TEAD inhibitors targeting the Hippo pathway exhibit antiproliferation in vitro and anti-tumor effect in vivo
Lead author: Ben Amidon, Ikena Oncology
Abstract #: 2474
Poster Board #: 18
Session: PO.MCB04.02 – Gene Regulation and Transcription Factors 2
Date and Time: Monday, June 22, 2020; 9:00 a.m. to 6:00 p.m. ET
URL: View Source!/9045/presentation/6122