8FJZ

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

Summary for 8FJZ

• Entry DOI: 10.2210/pdb8fjz/pdb
• Descriptor: Mitogen-activated protein kinase kinase kinase kinase 1, (3P)-3-{4-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]-6-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl}benzonitrile (3 entities in total)
• Functional Keywords: inhibitor, hematopoietic, kinase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 6
• Total formula weight: 225051.02

Authors

McTigue, M.,Johnson, E.,Cronin, C. (deposition date: 2022-12-20, release date: 2023-04-05, Last modification date: 2023-10-25)

Primary citation

Gallego, R.A.,Bernier, L.,Chen, H.,Cho-Schultz, S.,Chung, L.,Collins, M.,Del Bel, M.,Elleraas, J.,Costa Jones, C.,Cronin, C.N.,Edwards, M.,Fang, X.,Fisher, T.,He, M.,Hoffman, J.,Huo, R.,Jalaie, M.,Johnson, E.,Johnson, T.W.,Kania, R.S.,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, S.K.
Design and Synthesis of Functionally Active 5-Amino-6-Aryl Pyrrolopyrimidine Inhibitors of Hematopoietic Progenitor Kinase 1.
J.Med.Chem., 66:4888-4909, 2023

PubMed Abstract: 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 -factors and optimization of lipophilic efficiency.

PubMed: 36940470
DOI: 10.1021/acs.jmedchem.2c02038

Experimental method

X-RAY DIFFRACTION (1.897 Å)