Importantly, they also described the discovery of small molecules that irreversibly bound to this pocket on KRAS G12C – a finding that turned an undruggable target into a druggable one. Shokat and his colleagues at UCSF identified a new binding pocket, S-IIP, via crystallography studies. Despite decades of research focused on KRAS as a target of interest in oncology, it was generally deemed to be undruggable until 2013, when Dr. RAS proteins are the most frequently mutated oncoproteins, with KRAS being the most abundantly expressed RAS isoform. ERAS-801 is designed to be a potent, selective, reversible, and orally available small molecule with both: (1) highly enhanced CNS penetration (3.7:1 brain:plasma ratio in mice) and (2) the ability to target both EGFR alterations such as EGFRvIII, the most common mutant form of EGFR found in GBM, and wtEGFR, which heterodimerizes with EGFRvIII. The lack of clinical activity is likely multifactorial, but we believe there are two primary reasons why approved EGFR inhibitors are not effective: (1) the molecules do not penetrate the CNS well, and (2) the molecules are weak inhibitors of the EGFRvIII mutant protein as homodimers or heterodimers that include wildtype EGFR. However, the ability of these agents to effectively target wtEGFR and EGFRm in the CNS remains an unmet medical need. Targeting of wildtype EGFR (wtEGFR) and mutant variants of EGFR (EGFRm) by small molecules and antibodies has resulted in improved patient outcomes in NSCLC, CRC, and HNSCC. ERAS-801: our CNS-penetrant EGFR inhibitorĮGFR-mediated signaling plays a key role in the growth of many tumor types. Our SHP2 inhibitor is designed to block oncogenic signal transduction and delay the onset of resistance-thereby potentially serving as a backbone of combination therapy. SHP2 also drives tumor cell proliferation and development of resistance. The second prong of our first MAPKlamp, ERAS-601, is a potent, selective oral inhibitor of SHP2, a convergent node for upstream RTK signaling and a critical “on/off switch” that activates GTP-bound RAS signaling.
While providing proof-of-concept data, these trials may be expanded to enable potential accelerated approvals in their respective indications.
#GROOVE AGENT 4 TRIAL SERIES#
The first series of trials will be proof-of-concept studies in solid tumors, NSCLC, and CRC. We are pursuing a broad clinical development plan for ERAS-007 across multiple tumor types that includes both monotherapy and combinations with approved and investigational agents, such as RTK, SHP2, RAS, and/or RAF inhibitors. These findings support the development of ERAS-007 as a monotherapy or in combination in diverse, biomarker-selected tumor types. The adverse event profle was reversible, manageable, and consistent with ERK inhibition. Multiple objective responses were observed in patients with various tumor types, all of which harbor alterations (BRAF, HRAS, and NRAS) in the RAS/MAPK pathway, including melanoma, salivary gland cancer, NSCLC, and thyroid cancer.
#GROOVE AGENT 4 TRIAL TRIAL#
ERAS-007 has been evaluated as a single agent in a Phase 1 trial in patients with advanced solid tumors. ERAS-007ĮRAS-007 is the most potent ERK inhibitor in development and has the longest target residence time among ERK inhibitors that we are aware of.
We are planning to evaluate the molecule in indications where it has already shown promising clinical proof of concept – namely, NRASm melanoma and pan-RAS Q61X tissue agnostic solid tumors, as well as explore various combinations with other programs in our pipeline to target other RAS/MAPK pathway-driven tumors. Naporafenib is a potential first-in-class pan-RAF kinase inhibitor (with high potency and selectivity against BRAF and CRAF), and has been studied in over 500 patients to date.
#GROOVE AGENT 4 TRIAL DRIVERS#
We are also advancing multiple other programs targeting key oncogenic drivers in the RAS/MAPK pathway. These programs are examples of our innovative MAPKlamp strategy to target key upstream and downstream MAPK nodes. Our lead product candidates are naporafenib (ERAS-254, our oral pan-RAF inhibitor), ERAS-007 (our oral ERK1/2 inhibitor), and ERAS-601 (our oral SHP2 inhibitor).
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