8SC7

Structure of EGFR in complex with MTX-531

8SC7 の概要

• エントリーDOI: 10.2210/pdb8sc7/pdb
• 分子名称: Epidermal growth factor receptor, GLYCEROL, CHLORIDE ION, ... (5 entities in total)
• 機能のキーワード: egfr, dual egfr/pi3k inhibitor, transferase, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 38144.95

構造登録者

Whitehead, C.E.,Leopold, J. (登録日: 2023-04-05, 公開日: 2024-06-12, 最終更新日: 2024-12-25)

主引用文献

Whitehead, C.E.,Ziemke, E.K.,Frankowski-McGregor, C.L.,Mumby, R.A.,Chung, J.,Li, J.,Osher, N.,Coker, O.,Baladandayuthapani, V.,Kopetz, S.,Sebolt-Leopold, J.S.
A first-in-class selective inhibitor of EGFR and PI3K offers a single-molecule approach to targeting adaptive resistance.
Nat Cancer, 5:1250-1266, 2024

PubMed Abstract: Despite tremendous progress in precision oncology, adaptive resistance mechanisms limit the long-term effectiveness of molecularly targeted agents. Here we evaluated the pharmacological profile of MTX-531 that was computationally designed to selectively target two key resistance drivers, epidermal growth factor receptor and phosphatidylinositol 3-OH kinase (PI3K). MTX-531 exhibits low-nanomolar potency against both targets with a high degree of specificity predicted by cocrystal structural analyses. MTX-531 monotherapy uniformly resulted in tumor regressions of squamous head and neck patient-derived xenograft (PDX) models. The combination of MTX-531 with mitogen-activated protein kinase kinase or KRAS-G12C inhibitors led to durable regressions of BRAF-mutant or KRAS-mutant colorectal cancer PDX models, resulting in striking increases in median survival. MTX-531 is exceptionally well tolerated in mice and uniquely does not lead to the hyperglycemia commonly seen with PI3K inhibitors. Here, we show that MTX-531 acts as a weak agonist of peroxisome proliferator-activated receptor-γ, an attribute that likely mitigates hyperglycemia induced by PI3K inhibition. This unique feature of MTX-531 confers a favorable therapeutic index not typically seen with PI3K inhibitors.

PubMed: 38992135
DOI: 10.1038/s43018-024-00781-6

実験手法

X-RAY DIFFRACTION (1.984 Å)