science

TARGETING CANCER’S MOST commonly mutated pathway

Why RAS/MAPK?

There are approximately five million new cases of cancer per year with RAS/MAPK pathway alterations, most of which have limited or no treatment options. While the RAS/MAPK pathway has been well characterized and validated based on the development and approval of multiple compounds targeting discrete signaling nodes in the pathway, most of these compounds face resistance and tolerability challenges, highlighting the need for new approaches to target this important signaling cascade. The RAS/MAPK pathway is implicated in approximately one-third of all solid tumors, including colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and pancreatic ductal adenocarcinoma (PDAC).

MAPKlamp & More

Using innovative science and working with world-class collaborators, we are taking a holistic, modality-agnostic approach to effectively shut down the RAS/MAPK pathway. We are not just targeting individual signaling nodes. Rather, we seek to turn off multiple nodes and cooperative mechanisms along the pathway in parallel. To accomplish this, we are pursuing three therapeutic strategies that work together to comprehensively, and perhaps synergistically, shut down the RAS/MAPK pathway.

Our 3 therapeutic strategies

To learn more about our three therapeutic strategies and how they can help us overcome RAS/MAPK pathway-driven cancers, click on the numbers below.

Target upstream and downstream MAPK nodes

with single agents and
clamp oncogenic drivers (MAPKlamp^™) with combinations

Our proprietary MAPKlamp strategy targets upstream and downstream nodes of the RAS/MAPK pathway, initially SHP2 (ERAS-601) and ERK (ERAS-007), respectively, to shut down, or clamp, the signaling of various oncogenic drivers, such as RAS, RAF, and MEK alterations, trapped in between these nodes. With our MAPKlamp approach, we hope to induce tumor regression in RAS/MAPK pathway-driven cancers, while also blocking their main escape routes. We are also discovering and developing single agent and combination approaches to target other upstream nodes that impact the RAS/MAPK pathway such as EGFR (ERAS-801), a receptor tyrosine kinase that represents a key escape route for MAPK signaling, and SOS1 (ERAS-9), a guanine nucleotide exchange factor that enables RAS to cycle from the inactive GDP state to the active GTP state.

Target RAS directly

with single agents and combinations with
upstream, downstream,
and escape route targeted
therapies

Targeting RAS directly with single agents and combinations. We are discovering and developing molecules with the potential to inhibit RAS in its inactive GDP state as well as its more prevalent active GTP state. Utilizing our in-house discovery efforts employing structure-based drug design, we are developing a central nervous system (CNS)-penetrant inhibitor of KRAS G12C (ERAS-1), which is the only RAS isoform and mutation that is more commonly present in the inactive RAS-GDP state. We are also developing proprietary compounds against KRAS G12D (ERAS-4), which is more commonly found in the active RAS-GTP state and is the most prevalent KRAS mutation. Our approach to targeting other RAS isoforms and mutations also found more commonly in the RAS-GTP state is based on the foundational discoveries of one of our co-founders, Dr. Kevan Shokat, a world-renowned pioneer of novel therapeutic approaches targeting key cancer signaling pathways such as the RAS/MAPK pathway.

Target escape routes

enabled by other proteins
or pathways to further
disrupt RAS/MAPK
pathway signaling

Targeting escape routes enabled by other proteins or pathways to further disrupt RAS/MAPK pathway signaling. RAS-driven cancers utilize cooperative mechanisms to develop resistance. As an example, RAS-driven cancers can become dependent on autophagy, which becomes constitutively active and represents a potential escape route for metabolically active tumors such as pancreatic ductal adenocarcinoma. By targeting ULK (ERAS-5), a key regulator of autophagy, in combination with our RAS targeting agents, we aim to shut down this potential escape route for RAS-driven cancers. We also are actively pursuing various ways to further disrupt RAS/MAPK pathway signaling by degrading key proteins. Finally, MYC (ERAS-11) is a transcription factor and oncogene that is overexpressed in the majority of cancers and a key enabler of RAS/MAPK pathway signaling at the transcriptional level.

Our strategic focus on the RAS/MAPK pathway allows us to comprehensively target every critical node in the pathway that could drive signaling. In fact, we currently have programs targeting each of the nodes colored in purple below.

Presentations

ERAS-0015

ERAS-0015 is a pan-RAS molecular glue with best-in-class potential in RAS mutant solid tumors
Presented at the American Association for Cancer Research (AACR) Annual Meeting. April 2025.

ERAS-4001

ERAS-4001 is a pan-KRAS inhibitor with robust anti-tumor activity in KRAS altered solid tumors
Presented at the American Association for Cancer Research (AACR) Annual Meeting. April 2025.

Naporafenib (ERAS-254)

ERAS-007

ERAS-601

DISCOVERY

Identification and characterization of inhibitors of SHOC2-MRAS-PP1C complex assembly
Presented at the American Association for Cancer Research (AACR) Annual Meeting. April 2025.