9U8C
Crystal structure of EGFR exon20 insertion mutant in complex with enozertinib (ORIC-114)
This is a non-PDB format compatible entry.
Summary for 9U8C
| Entry DOI | 10.2210/pdb9u8c/pdb |
| Descriptor | Epidermal growth factor receptor, ~{N}-[5-[[6-[(3~{R})-3-[3,5-bis(fluoranyl)phenyl]-1,2-oxazolidin-2-yl]pyrimidin-4-yl]amino]-2-[4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl]-4-methoxy-phenyl]propanamide (2 entities in total) |
| Functional Keywords | kinase oric-114, signaling protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 5 |
| Total formula weight | 194908.08 |
| Authors | |
| Primary citation | Junttila, M.R.,Repellin, C.E.,Salaniwal, S.,Warne, R.,Lee, Y.,Kim, H.,Seo, K.A.,Lee, Y.,Jung, H.R.,Baik, J.,Chang, J.H.,Andreatta, G.,Long, J.E.,Sun, J.D.,Ni, S.W.,Soroceanu, L.,Sambucetti, L.C.,Das, A.,Chan, B.,Narayanan, P.,Pereira, A.S.,Chow Maneval, E.,Multani, P.S.,Patel, R.,Panuwat, M.,Blank, B.R.,Ndubaku, C.,Romero, F.A.,Daemen, A.,Spira, A.I.,Friedman, L.S. Enozertinib Is a Selective, Brain-Penetrant EGFR Inhibitor for Treating Non-Small Cell Lung Cancers with EGFR Exon 20 and Atypical Mutations. Cancer Res., 86:759-772, 2026 Cited by PubMed Abstract: EGFR mutations are common oncogenic drivers in non-small cell lung cancer (NSCLC), and around one-third of patients develop brain metastases over the course of their disease. Patients with non-classical EGFR mutations, such as insertions in exon 20, are a high unmet need with a worse prognosis compared to patients with classical EGFR mutations. Here, we describe the discovery and development of enozertinib (formerly ORIC-114), a highly brain-penetrant, orally bioavailable, irreversible inhibitor that targets EGFR exon 20 mutations with unparalleled kinome selectivity. Preclinical studies revealed strong potency and tumor regressions driven by enozertinib across a broad range of atypical EGFR mutant models. In a phase I clinical trial of enozertinib in patients with advanced NSCLC bearing atypical mutations in EGFR, a patient with harboring an EGFR exon 20 insertion experienced sustained complete response of all systemic and brain metastases. Together, these findings identify enozertinib as a promising investigational inhibitor to meet the unmet need for brain-penetrant therapies for NSCLC with EGFR exon 20 insertions or other atypical mutations. PubMed: 41196054DOI: 10.1158/0008-5472.CAN-25-3502 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.5 Å) |
Structure validation
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