9bi8

Crystal structure of inhibitor GNE-6893 bound to HPK1

spinqualitylabelsall models 9bi8, resolution 2.25Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9bi8 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.25Å Ligands: A1APL, DMS, NA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function M4K1_HUMAN Serine/threonine-protein kinase, which may play a role in the response to environmental stress. Appears to act upstream of the JUN N-terminal pathway. May play a role in hematopoietic lineage decisions and growth regulation. Able to autophosphorylate. Publication Abstract from PubMed 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 in vitro 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 muM), a favorable in vitro safety profile, and good projected human pharmacokinetics. Discovery of GNE-6893, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of HPK1.,Tellis JC, Wei B, Siu M, An L, Chan GK, Chen Y, Du X, Gazzard L, Hu B, Kiefer J, Kakiuchi-Kiyota S, Lainchbury M, Linehan JL, Luo X, Malhotra S, Mendonca R, Pang J, Ran Y, Sethuraman V, Seward E, Sneeringer C, Su D, Wang W, Wu P, Moffat JG, Heffron TP, Choo EF, Chan BK ACS Med Chem Lett. 2024 Sep 3;15(9):1606-1614. doi: , 10.1021/acsmedchemlett.4c00319. eCollection 2024 Sep 12. PMID:39291002 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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