9QT6
Crystal structure of HPK1 T165E/S171E in complex with pyrazine carboxamide inhibitor
This is a non-PDB format compatible entry.
Summary for 9QT6
| Entry DOI | 10.2210/pdb9qt6/pdb |
| Descriptor | Mitogen-activated protein kinase kinase kinase kinase 1, 3-[(1,3-dimethylpyrazol-4-yl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 1,2-ETHANEDIOL, ... (4 entities in total) |
| Functional Keywords | transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 33402.71 |
| Authors | Schimpl, M. (deposition date: 2025-04-08, release date: 2025-05-28, Last modification date: 2025-09-03) |
| Primary citation | Metrano, A.J.,Morrill, L.A.,Bommakanti, G.,Casella, R.,Cook, S.,Escobar, R.A.,Giblin, K.A.,Gosselin, E.,Grebe, T.,Hariparsad, N.,Howells, R.,Lamont, G.M.,Mele, D.A.,Pflug, A.,Proia, T.A.,Rezaei, H.,Richter, M.,Richards, R.,San Martin, M.,Schimpl, M.,Schuller, A.G.,Sha, L.,Sheppeck 2nd, J.E.,Song, K.,Tang, H.,Wagner, D.J.,Wang, J.,Wu, A.,Wu, D.,Wu, Y.,Xu, K.,Ye, M.,Shields, J.D.,Grimster, N.P. Synthetic chemistry enabling the discovery and development of a series of pyrazoles as HPK1 inhibitors. Rsc Med Chem, 16:3522-3529, 2025 Cited by PubMed Abstract: Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T-cell signaling. Inhibition of HPK1 with small molecules has been shown to reinvigorate the immune system toward fighting tumours in preclinical models, thus it holds promise as a therapeutic strategy in cancer immunotherapy. Herein we report a series of pyrazine carboxamide pyrazoles as selective inhibitors of HPK1. Key to our approach was the development of late-stage functionalisation chemistry which allowed for rapid SAR generation. Through these efforts, we discovered difluoroethyl pyrazole 16a, an tool which elicited the desired pharmacodynamic response in mice. Further, we describe the optimization of synthetic chemistry which could support preclinical studies of a member of this series of substituted pyrazoles. PubMed: 40521343DOI: 10.1039/d5md00309a PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.76 Å) |
Structure validation
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