Hippo Signaling Pathway Program

IK-930, an oral small molecule inhibitor of a transcription factor known as TEAD, targets a key tumor suppressor axis with tumor cell intrinsic dependence and immunomodulatory mechanisms of action, and is in IND-enabling studies.

Hippo Signaling Pathway Program

IK-930, an oral small molecule inhibitor of a transcription factor known as TEAD, targets a key tumor suppressor axis with tumor cell intrinsic dependence and immunomodulatory mechanisms of action.

IK-930

The Hippo pathway is a critical signal transduction pathway that regulates cell fate, polarity, proliferation, and survival, as well as organ size and tissue homeostasis. Aberrant activation of TEAD caused by mutations in the Hippo tumor suppressor pathway can drive the formation and survival of tumors and the development of resistance to multiple existing therapies. The Hippo pathway is widely accepted as a key and prevalent driver of cancer pathogenesis and is genetically altered in approximately 10% of all cancers, and such genetic alterations are generally associated with poor patient outcomes.

In certain tumors, such as mesothelioma and epithelioid hemangioendothelioma, or EHE, a type of soft tissue sarcoma, genetic alterations in the Hippo pathway are found in over 40% of patients. Activated Hippo signaling correlates with poor patient outcomes in a number of cancers. Moreover, the Hippo pathway has been shown to promote immune evasion via multiple mechanisms.

When the Hippo pathway is inactivated, the transcriptional coactivators YAP and TAZ are stabilized, translocate into the cell nucleus and bind to the TEAD transcription factor to drive transcription of multiple genes involved in tumor initiation and progression, cancer metastasis, and therapeutic resistance. It has been demonstrated that acquired Tyrosine Kinase Inhibitor (TKI) resistance is dependent upon increased YAP/TAZ-TEAD transcription via direct activation to bypass BRAF. Inhibition of TEAD can lead to restored TKI sensitivity.

IK-930 is designed to potently and selectively bind to TEAD and inhibit TEAD- dependent gene expression. Ikena intends to submit an IND in the second half of 2021. Ikena intends to pursue clinical development of IK-930 across a wide range of tumor types with known Hippo pathway genetic alterations, and plan to focus our initial development efforts on indications such as mesothelioma and soft tissue sarcomas, that provide the potential for rapid clinical development to achieve proof-of-concept in disease indications with high unmet medical need.

Moreover, we believe there is potential for a tumor agnostic approach for IK-930 given the prevalence of Hippo pathway genetic alterations in many forms of cancers. We also plan to explore IK-930 in combination with other targeted therapies, such as epidermal growth factor receptor, or EGFR, inhibitors, in more prevalent tumor indications.

Our pipeline includes patient-directed targeted oncology and tumor microenvironment programs.