TEAD

Pan-TEAD Inhibitor:

Treating Mesothelioma, and Solid Tumors (Phase I)

Assays Completed

Wholly-owned and Available for Licensing

• In vivo efficacy studies – Single agent

• In vivo PK-PD

• In vivo PK studies

• In vitro ADMET studies

Developability/CMC

• In vitro cell-based

• Toxicology studies

• Enzymatic

Target Rationale

The TEAD family of transcription factors (TEAD1/2/3/4) are master regulators in oncogenesis and drug resistance through YAP/TAZ. YAP/TAZ are critical activators of all TEAD isoforms. These isoforms have an overlapping function in tumor biology. Given the compensatory roles of various TEAD isoforms, Pan-TEAD inhibition is hypothesized to have optimal anti-tumor efficacy. This makes it an interesting approach that can be potentially combined with targeted therapy, chemotherapy, and immunotherapy in solid tumors, and as a monotherapy for Mesothelioma (Hippo pathway mutations).

TEAD-YAP/TAZ forms an oncogenic complex that is primarily regulated by the Hippo pathway.

Expert Opin Ther Pat. 2018 Dec;28(12):867-873. doi : 10.1080/13543776.2018.1549226.

Insilico Medicine Pan-TEAD Inhibitor Summary – Phase I

Novel structure generated by AI

Novel structure generated by Insilico Medicine's AI small molecule generation platform Chemistry 42

Effective therapy for treating solid tumors

• Potential best-in-class pan TEAD inhibitor (Non-covalent palmitoylation inhibitor) with a novel IP protected molecule
• Exhibited potent in vitro and in vivo anti-cancer activities in Hippo-mutant mesothelioma models, along with excellent ADME

Promising drug-ability as an oral agent

• Potent orally available TEAD inhibitor exhibits robust anti-tumor activity in hippo-pathway deficient mesothelioma models
• Excellent DMPK profiles, broad therapeutic index and good developability

Significantly higher safety margin

• Overall good tolerability up to high doses in rodent and dog models, based on GLP-tox studies
• Exhibits favorable PK and safety profiles

Indication

Mesothelioma, epithelioid hemangioendothelioma (EHE), meningioma, glioblastoma, liposarcoma, and pancreatic cancers

• These cancers often have loss-of-function mutations in the NF2 gene, which encodes for Merlin, a protein that activates the Hippo pathway and inhibits YAP/TAZ-TEAD-mediated gene transcription. By blocking TEAD, inhibitors aim to restore the balance of the Hippo pathway and prevent the proliferation and survival of tumor cells. These cancers can benefit from Pan-TEAD inhibitors.

• ISM6331 is a potent pan-TEAD non-covalent inhibitor with a novel scaffold developed from Chemistry42, that has the potential to serve as a therapeutic approach for solid tumors in multiple cancer types resistant to current therapies.

Broad Therapeutic Opportunities in Combination Therapy

• Combination with target therapy, chemotherapy and immunotherapy drugs for solid tumors treatment including EGFR and KRAS mutant Non-small cell lung cancer (NSCLC), Colorectal cancer (CRC), Pancreatic cancer(PDAC) and other solid tumors.

Project Highlight

ISM developed an AI-designed novel pan-TEAD inhibitor targeting TEAD's lipid binding site. This inhibitor exhibited potent in vitro and in vivo anti-cancer activities in Hippo-mutant mesothelioma models, along with excellent ADME. It exhibited favorable preclinical PK and safety profiles that includes; very low off-target risk in Safety 44 test, low risk for drug-drug interaction, clean profile in hERG, with low clearance, and excellent oral bioavailability. Additionally, it also exhibited excellent in vivo efficacy, and tolerability. The Pan-TEAD inhibitor also significantly suppressed TEAD-target gene expression (CCN1 and CCN2) in a dose dependent manner.

Promising anti-tumor efficacy in a dose-dependent manner without body weight loss in the MSTO-211H CDX mouse model.