The Wnt/β-catenin signaling pathway is one of the most frequently activated pathways in cancer, with highly prevalent mutations occurring in colorectal, hepatocellular, and endometrial tumors, among others. Metastatic colorectal cancer is a devastating malignancy that is becoming increasingly common in younger people, with no approved therapies that directly target the principal oncogenic driver mutations. Patients are in desperate need of effective, novel therapeutic options.

FOG-001 is a first-in-class, TCF-blocking β-catenin inhibitor that directly blocks the key oncogenic driver of the Wnt/β-catenin signaling pathway, unlike any previously reported Wnt/β-catenin pathway modulators. FOG-001 acts inside the cell, where it binds to β-catenin, which lies at or just downstream of the most common mutations in the pathway. By disrupting the interaction between β-catenin and the transcription factor TCF, FOG-001 inhibits the signaling by which Wnt pathway mutations are believed to drive oncogenesis. This is in contrast to past attempts to drug the Wnt/β-catenin pathway, which act upstream of the most common pathway mutations and are thus unable to block activated signaling in most patients. 

In biochemical and cellular studies, FOG-001 has been shown to potently and selectively disrupt the interaction of β-catenin with TCF. In vivo studies using patient-derived xenograft models of Wnt/β-catenin pathway-activated tumors have demonstrated the ability of FOG-001 to cause complete tumor growth inhibition and tumor regressions. 

FOG-001 is currently being evaluated in a first-in-human Phase 1/2 clinical trial in patients with Wnt/β-catenin signaling pathway-activated advanced or metastatic solid tumors.

ERG is one of the most frequently overexpressed oncogenes in prostate cancer, and has remained beyond therapeutic reach. In approximately 40% of prostate tumors, the ERG gene fuses with another gene called TMPRSS2, which is under the control of the androgen receptor. This leads to the overproduction of the ERG-TMPRSS2 fusion protein, which in turn leads to a poor prognosis in patients, as high levels of ERG is one of the key factors in transforming localised, aggressive cancer into metastatic cancer. Aberrant activation of ERG via these genetic fusion events also activates its downstream transcription targets and promotes tumor growth.  

Fog’s ERG program is designed to block or destroy ERG function in ERG-fusion-positive prostate cancers. Prostate cancer represents a significant unmet need in a large patient population, with more than 50,000 new patients being diagnosed annually across the globe. ERG is also implicated in aggressive Acute Myeloid Leukemia (AML).

The cyclin family of proteins play an important role in regulating the cell cycle. Among the members of this family, Cyclin E regulates multiple downstream molecules by interacting with cyclin-dependent kinases (CDKs). Cyclin E is frequently amplified in ovarian cancer, esophagogastric adenocarcinoma, and endometrial carcinoma. Studies have shown that Cyclin E is implicated in the resistance of tumor cells to chemotherapy, and that its expression in tumor cells is closely related to prognosis: high expression of Cyclin E1 is associated with poor response to existing CDK4/6 inhibitors, while Cyclin E1/2 amplifications represent resistance mechanisms to CDK4/6 inhibitors in HR+/HER2– advanced breast cancer​.

Fog’s Cyclin E1/2 degrader program represents a unique therapeutic mechanism targeting Cyclin E1/2 amplified and overexpressed tumor types, and holds the promise of being a transformational therapy in those patients where Cyclin E is a driver of cancer​.

Indications:

• AR dependent prostate cancer

Gain-of-function mutations of the RAS family of oncogenes (HRAS, KRAS, NRAS) are found in ~25% of human cancers. In normal cells, RAS is activated by upstream membrane-bound growth factor receptors, such as the EGFR family. In cancer cells, gain-of-function mutations increase levels of the GTP-bound active state of RAS and activate downstream growth and survival signaling pathways.

RAS mutations are isoform, hotspot and tumor type specific. KRAS is the most frequently mutated of all three RAS isoforms and is frequently mutated in lung, colorectal and pancreatic cancers, among others.

Despite the recent success of KRAS G12C-specific inhibitors in the clinic, significant unmet medical need remains. The KRAS G12C mutation represents only ~20% of all KRAS mutations and less than 10% of all RAS mutations. Moreover, on-target resistance mutations have been reported for first generation KRAS G12C-specific inhibitors. A pan-KRAS inhibitor could target a broad spectrum of mutations, including resistance mutations.