9BLG
Crystal structure of non-receptor protein tyrosine phosphatase SHP2 in complex with PF-07284892
This is a non-PDB format compatible entry.
Summary for 9BLG
| Entry DOI | 10.2210/pdb9blg/pdb |
| Descriptor | 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) |
| Functional Keywords | phosphatase, inhibitor, shp2, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 125059.87 |
| Authors | |
| Primary citation | 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 Cited by 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: 37269335DOI: 10.1158/2159-8290.CD-23-0361 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.06 Å) |
Structure validation
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