Summary for 9BI8
| Entry DOI | 10.2210/pdb9bi8/pdb |
| Descriptor | Mitogen-activated protein kinase kinase kinase kinase 1, (3R,4S)-4-methyloxolan-3-yl [(6P)-8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl]carbamate, DIMETHYL SULFOXIDE, ... (5 entities in total) |
| Functional Keywords | hpk1, map4k1, cancer, pharmacology, kinase, inhibitor, signaling protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 71044.92 |
| Authors | Kiefer, J.R.,Tellis, J.C.,Chan, B.K.,Wang, W.,Wu, P.,Choo, E.F.,Heffron, T.P.,Wei, B.,Siu, M. (deposition date: 2024-04-22, release date: 2024-10-02) |
| Primary citation | Tellis, J.C.,Wei, B.,Siu, M.,An, L.,Chan, G.K.,Chen, Y.,Du, X.,Gazzard, L.,Hu, B.,Kiefer, J.,Kakiuchi-Kiyota, S.,Lainchbury, M.,Linehan, J.L.,Luo, X.,Malhotra, S.,Mendonca, R.,Pang, J.,Ran, Y.,Sethuraman, V.,Seward, E.,Sneeringer, C.,Su, D.,Wang, W.,Wu, P.,Moffat, J.G.,Heffron, T.P.,Choo, E.F.,Chan, B.K. Discovery of GNE-6893, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of HPK1. Acs Med.Chem.Lett., 15:1606-1614, 2024 Cited by PubMed Abstract: Hematopoietic progenitor kinase 1 (HPK1) serves a key immunosuppressive role as a negative regulator of T-cell receptor (TCR) signaling. HPK1 loss-of-function is associated with augmentation of immune function and has demonstrated synergy with immune checkpoint inhibitors in syngeneic mouse cancer models. These data offer compelling evidence for the use of selective small molecule inhibitors of HPK1 in cancer immunotherapy. We identified a novel series of isoquinoline HPK1 inhibitors through fragment-based screening that displayed promising levels of biochemical potency and activity in functional cell-based assays. We used structure-based drug design to introduce key selectivity elements while simultaneously addressing pharmacokinetic liabilities. These efforts culminated in a molecule demonstrating subnanomolar biochemical inhibition of HPK1 and strong augmentation of TCR signaling in primary human T-cells. Further profiling of this molecule revealed excellent kinase selectivity (347/356 kinases <50% inhibition @ 0.1 μM), a favorable safety profile, and good projected human pharmacokinetics. PubMed: 39291002DOI: 10.1021/acsmedchemlett.4c00319 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.25 Å) |
Structure validation
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