FOG-001, a first-and-only-in-class direct β-catenin inhibitor

Dysregulation of the Wnt/β-catenin signaling pathway has been shown to occur in at least 20% of all human cancers. In the U.S. alone, FOG-001 has the potential to become a new treatment option for >1 million patients.

In biochemical and cellular studies, FOG-001 has been shown to potently, precisely and selectively disrupt the interaction of β-catenin with its obligate transcription factor, TCF. Preclinical studies have demonstrated the ability of FOG-001 to cause tumor growth inhibition and regression by disrupting β-catenin-dependent signaling.

FOG-001 is the inaugural member of FogPharma’s TCF-Catenix family of direct-acting β-catenin antagonists and combines key features that distinguish it from previously reported Wnt/β-catenin pathway modulators: FOG-001 acts inside the cell, where it directly binds the key oncogenic driver β-catenin; and FOG-001 blocks TCF-β-catenin engagement at the most downstream node in the canonical Wnt pathway, thus abrogating the signal transmission mechanism by which most, if not all, known Wnt pathway mutations are believed to drive oncogenesis.

FogPharma plans to submitan investigational new drug (IND) application for FOG-001 to the U.S. Food and Drug Administration (FDA) and initiate clinical development by mid-2023.

First-in-class YAP/TAZ-blocker TEAD antagonist program

TEAD is a transcription factor that functions as the terminal effector of the Hippo pathway. The pathway is activated by interaction between TEAD and co-activator proteins of the YAP1 and TAZ family. The Hippo pathway is aberrantly activated via genetic alterations in multiple cancer types, from mesothelioma and squamous cell cancers to gliomas and sarcomas to tumors of the esophagus, endometrium, skin and stomach.

Interactions between TEAD and YAP1/TAZ contribute to tumor growth, maintenance and progression as tumor-intrinsic oncogenic drivers and also provide resistance mechanisms to drug treatments, in addition to serving as regulators of immunity and tumor microenvironment leading to immunosuppression. A molecule to block fully activated TEAD binding to YAP1/TAZ would potentially provide benefit to patients as a single agent in tumors with oncogenic driver mutations, as a single agent or combination partner in drug resistance diseases and as a combination partner by promoting antitumor immunity.

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. NRAS is the 2nd most frequently mutated RAS isoform and NRAS mutations are most commonly found in cutaneous melanoma and acute myeloid leukemia. Fog is developing first-in-class NRAS inhibitors targeting tumors with NRAS Q61 mutations.

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.

Aberrant fusions of ETS family transcription factors (ERG, ETV1, ETV4, FLI) are detected in ~60% of prostate cancer patients​. ERG fusions, detected in ~50% patients, are the most frequent of all and TMPRSS2 is the most frequent 5’ fusion partner. Fusion formation is driven by androgen activation of the androgen receptor (AR) and the concurrent recruitments of genes such as TOP2B facilitating double strand breaks (DSB) and DSB repair by non-homologous end joining (NHEJ)​.

AR binds to the promoters of fusion genes and activates transcription and downstream transcription targets.​ Somatic mutations of PI3K/AKT pathway genes, with PTEN loss as the most frequent event, are co-occurring with ETS fusions in prostate cancer​. ERG fusion and PTEN loss drive initiation and progression of prostate cancer via diverse cancer pathways​.

FogPharma is developing an ERG transcription inhibitor targeting ERG-fusion-positive prostate cancers.

Cyclin E (CCNE1, CCNE2) forms complexes with CDK2 and functions as a cell cycle regulator. Activated Cyclin E/CDK2 complexes drives cell cycle progression from G1 to S phase.​

In cancer, the Cyclin E/CDK2 complex is aberrantly activated through Cyclin E amplification and overexpression. CCNE1 is most frequently amplified in ovarian cancer (19%), esophagogastric adenocarcinoma (11.5%) and endometrial carcinoma (11%)​. Additionally, CCNE1 high expression is associated with relatively worse response to CDK4/6 inhibitors and CCNE1/2 amplifications represent resistance mechanisms to CDK4/6 inhibitors​.

A CCNE1 degrader represents a unique therapeutic mechanism targeting Cyclin E1 amplified and overexpressed tumor types​.