Oncogenic mutations in the RAS family of genes (KRAS, HRAS, and NRAS) are present in approximately 30% of cancer. RAS plays a pivotal role in signal transduction pathways leading to tumor cell proliferation and survival. ADT’s program has identified novel small molecules that exhibit potent and selective inhibition of activated RAS signaling regardless of isoform or mutation, or pan-RAS inhibition.
Historically, direct inhibition of RAS has been challenging. However, investigational compounds that selectively target the KRAS G12C mutation recently have shown antitumor activity in the clinic, clinically validating RAS as a therapeutic target. These current investigational drugs are mutation specific—with G12C representing approximately 11% of KRAS mutations in cancer. A broadly active pan-RAS inhibitor with the potential to treat RAS-driven cancers regardless of RAS isoform or mutation would be clinically useful.
The RAS inhibitor program is comprised of a novel series of indene derivatives that potently, selectively and reversibly inhibit growth of tumor cells harboring mutant RAS, while having greater than 100-fold selectivity over cells with normal RAS activity. Inhibitory activity has been observed with low nanomolar potency in KRAS-, HRAS-, and NRAS-driven tumor cell models with a variety of mutations across a variety of tumor types. These compounds inhibit downstream signaling through RAF and PI3K pathways, initiate cell-cycle arrest and induce apoptosis, demonstrated blockade of GTP loading of RAS in the nucleotide-free state in cell-free biochemical assays, and have exhibited in vivo activity in RAS mutant tumor models. They have potential for RAS inhibition is a broad variety of clinical settings.
Genetic alterations in components that make up the Wnt signaling pathway, which includes APC (adenomatous polyposis coli) and β-catenin, are prevalent in a number of cancer types, occurring in upwards of 80% of colorectal cancers. Additionally, germline mutations of APC lead to the hereditary cancer syndrome Familial Adenomatous Polyposis (FAP). Wnt signaling controls the level of intracellular activated β-catenin, a key effector of oncogenic signal transduction, and oncogenic alterations in Wnt, APC, or β-catenin all result in elevated and uncontrolled levels of β-catenin. Recent studies have shown that the cyclic nucleotide phosphodiesterase 10A (PDE10) is overexpressed during early stages of tumorigenesis and is essential for tumor cell growth. PDE10 inhibition activates protein kinase G and leads to the degradation of the oncogenic pool of β-catenin to suppress critical proteins essential for tumor cell proliferation and survival. Thus, targeting PDE10 provides a novel approach to selectively suppress β-catenin-mediated transcriptional activity.
ADT’s program has identified small molecules that selectively and potently inhibit PDE10 and suppress Wnt/β-catenin signaling in preclinical models. PDE10 inhibition has been shown to downregulate β-catenin expression, and inhibits polyp and tumor growth. It has potential for application in the treatment of cancer as well as spontaneous and familial polyposis syndromes.
[i] NCI RAS initiative website https://www.cancer.gov/research/key-initiatives/ras.
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