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8fko

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Crystal structure of HPK1 kinase domain T165E,S171E phosphomimetic mutant in complex with 3-{4-[(2S,5R)-5-Amino-2-methylpiperidin-1-yl]-6-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl}benzonitrile

Structural highlights

8fko is a 6 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 2.104Å
Ligands:
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.^[1] ^[2]

Publication Abstract from PubMed

Immune activating agents represent a valuable class of therapeutics for the treatment of cancer. An area of active research is expanding the types of these therapeutics that are available to patients via targeting new biological mechanisms. Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of immune signaling and a target of high interest for the treatment of cancer. Herein, we present the discovery and optimization of novel amino-6-aryl pyrrolopyrimidine inhibitors of HPK1 starting from hits identified via virtual screening. Key components of this discovery effort were structure-based drug design aided by analyses of normalized B-factors and optimization of lipophilic efficiency.

Design and Synthesis of Functionally Active 5-Amino-6-Aryl Pyrrolopyrimidine Inhibitors of Hematopoietic Progenitor Kinase 1.,Gallego RA, Bernier L, Chen H, Cho-Schultz S, Chung L, Collins M, Del Bel M, Elleraas J, Costa Jones C, Cronin CN, Edwards M, Fang X, Fisher T, He M, Hoffman J, Huo R, Jalaie M, Johnson E, Johnson TW, Kania RS, Kraus M, Lafontaine J, Le P, Liu T, Maestre M, Matthews J, McTigue M, Miller N, Mu Q, Qin X, Ren S, Richardson P, Rohner A, Sach N, Shao L, Smith G, Su R, Sun B, Timofeevski S, Tran P, Wang S, Wang W, Zhou R, Zhu J, Nair SK J Med Chem. 2023 Mar 20. doi: 10.1021/acs.jmedchem.2c02038. PMID:36940470^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Wang H, Chen Y, Lin P, Li L, Zhou G, Liu G, Logsdon C, Jin J, Abbruzzese JL, Tan TH, Wang H. The CUL7/F-box and WD repeat domain containing 8 (CUL7/Fbxw8) ubiquitin ligase promotes degradation of hematopoietic progenitor kinase 1. J Biol Chem. 2014 Feb 14;289(7):4009-17. doi: 10.1074/jbc.M113.520106. Epub 2013 , Dec 20. PMID:24362026 doi:http://dx.doi.org/10.1074/jbc.M113.520106
↑ Hu MC, Qiu WR, Wang X, Meyer CF, Tan TH. Human HPK1, a novel human hematopoietic progenitor kinase that activates the JNK/SAPK kinase cascade. Genes Dev. 1996 Sep 15;10(18):2251-64. PMID:8824585
↑ Gallego RA, Bernier L, Chen H, Cho-Schultz S, Chung L, Collins M, Del Bel M, Elleraas J, Costa Jones C, Cronin CN, Edwards M, Fang X, Fisher T, He M, Hoffman J, Huo R, Jalaie M, Johnson E, Johnson TW, Kania RS, Kraus M, Lafontaine J, Le P, Liu T, Maestre M, Matthews J, McTigue M, Miller N, Mu Q, Qin X, Ren S, Richardson P, Rohner A, Sach N, Shao L, Smith G, Su R, Sun B, Timofeevski S, Tran P, Wang S, Wang W, Zhou R, Zhu J, Nair SK. Design and Synthesis of Functionally Active 5-Amino-6-Aryl Pyrrolopyrimidine Inhibitors of Hematopoietic Progenitor Kinase 1. J Med Chem. 2023 Apr 13;66(7):4888-4909. PMID:36940470 doi:10.1021/acs.jmedchem.2c02038