8SC8
Structure of PI3KG in complex with MTX-531
Summary for 8SC8
| Entry DOI | 10.2210/pdb8sc8/pdb |
| Descriptor | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, SULFATE ION, N-[(5P)-2-chloro-5-(4-{[(1R)-1-phenylethyl]amino}quinazolin-6-yl)pyridin-3-yl]methanesulfonamide, ... (4 entities in total) |
| Functional Keywords | pi3kg, dual egfr/pi3k inhibitor, transferase, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 111661.36 |
| Authors | Whitehead, C.E.,Leopold, J. (deposition date: 2023-04-05, release date: 2024-06-12, Last modification date: 2024-12-25) |
| Primary citation | 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 Cited by 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: 38992135DOI: 10.1038/s43018-024-00781-6 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.687 Å) |
Structure validation
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