9BLG

Crystal structure of non-receptor protein tyrosine phosphatase SHP2 in complex with PF-07284892

これはPDB形式変換不可エントリーです。

9BLG の概要

• エントリーDOI: 10.2210/pdb9blg/pdb
• 分子名称: Tyrosine-protein phosphatase non-receptor type 11, (1S)-1'-{6-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-1,2,4-triazin-3-yl}-1,3-dihydrospiro[indene-2,4'-piperidin]-1-amine (3 entities in total)
• 機能のキーワード: phosphatase, inhibitor, shp2, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 125059.87

構造登録者

Bester, S.M.,Wu, W.-I.,Mou, T.-C. (登録日: 2024-04-30, 公開日: 2024-05-29)

主引用文献

Drilon, A.,Sharma, M.R.,Johnson, M.L.,Yap, T.A.,Gadgeel, S.,Nepert, D.,Feng, G.,Reddy, M.B.,Harney, A.S.,Elsayed, M.,Cook, A.W.,Wong, C.E.,Hinklin, R.J.,Jiang, Y.,Brown, E.N.,Neitzel, N.A.,Laird, E.R.,Wu, W.I.,Singh, A.,Wei, P.,Ching, K.A.,Gaudino, J.J.,Lee, P.A.,Hartley, D.P.,Rothenberg, S.M.
SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy.
Cancer Discov, 13:1789-1801, 2023

PubMed Abstract: Rationally targeted therapies have transformed cancer treatment, but many patients develop resistance through bypass signaling pathway activation. PF-07284892 (ARRY-558) is an allosteric SHP2 inhibitor designed to overcome bypass-signaling-mediated resistance when combined with inhibitors of various oncogenic drivers. Activity in this setting was confirmed in diverse tumor models. Patients with ALK fusion-positive lung cancer, BRAFV600E-mutant colorectal cancer, KRASG12D-mutant ovarian cancer, and ROS1 fusion-positive pancreatic cancer who previously developed targeted therapy resistance were treated with PF-07284892 on the first dose level of a first-in-human clinical trial. After progression on PF-07284892 monotherapy, a novel study design allowed the addition of oncogene-directed targeted therapy that had previously failed. Combination therapy led to rapid tumor and circulating tumor DNA (ctDNA) responses and extended the duration of overall clinical benefit.

PubMed: 37269335
DOI: 10.1158/2159-8290.CD-23-0361

実験手法

X-RAY DIFFRACTION (2.06 Å)