Small Molecule Pan-RAS Inhibitors

Oncogenic mutations in the RAS family of genes (KRAS, HRAS, and NRAS) are present in approximately 30% of cancer. Figure 1 below illustrates the proportion of RAS mutations found in common tumor types. RAS plays a pivotal role in signal transduction pathways leading to tumor cell proliferation and survival. Our 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 have shown antitumor activity in the clinic, providing clinical validation of RAS as a therapeutic target. These current investigational drugs are mutation specific—with G12C representing approximately 11% of KRAS mutations in cancer. While KRAS represents the most commonly mutated isoform of RAS (see Figure 1), there is a spectrum of activating mutations that have been observed with this isoform (see Figure 2). A variety of activating mutations have also been observed with the HRAS and NRAS isoforms.

The RAS inhibitor program is comprised of  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 (<10 nM) in KRAS-, HRAS-, and NRAS-driven models with a variety of mutations (e.g. KRAS G12C, G13D, G12V, G12S; HRAS G12D; and NRAS Q61K) across a variety of tumor types. These compounds inhibit downstream signaling through RAF and PI3K pathways, initiate cell-cycle, arrest and induce apoptosis, demonstrate 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. We believe these molecules have potential for RAS inhibition in a broad variety of clinical settings. 

Figure 1: Frequency of RAS Mutations by Tumor Type

Human cancers with >5% RAS mutation frequency

Adapted from: Cox et al., Nat Rev Drug Discov, 2014

Figure 2: Frequency of Specific KRAS mutations in KRAS-Mutated Lung, Colorectal, Pancreatic and Biliary Tract Cancers

Adapted from: Vasan et al.,  Clinical cancer research, 2014. 

Publications

Novel RAS Inhibitor, MCI-062, potently and selectively inhibits the growth of KRAS mutant pancreatic tumor cells by blocking GTP loading of RAS. Mattox et al. AACR Annual Meeting 2019. [Download Poster]

Targeting RAS and downstream signaling in high-grade serious ovarian carcinoma with novel RAS inhibitors. Mattox et al. AACR Annual Meeting 2019. [Download Poster] 

A novel RAS Inhibitor, MCI-062, Inhibits Colon Tumor Growth in vivo and Activates Antitumor Immunity. Keeton et al. AACR Annual Meeting 2019.