7M0M

HPK1 IN COMPLEX WITH COMPOUND 1

7M0M の概要

• エントリーDOI: 10.2210/pdb7m0m/pdb
• 分子名称: Mitogen-activated protein kinase kinase kinase kinase 1, 4-[2-fluoro-6-(trifluoromethyl)anilino]-2-[(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]pyrimidine-5-carboxamide (3 entities in total)
• 機能のキーワード: hpk1 hematopoietic progenitor kinase, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 66783.32

構造登録者

Lesburg, C.A. (登録日: 2021-03-11, 公開日: 2021-04-07, 最終更新日: 2024-04-03)

主引用文献

Vara, B.A.,Levi, S.M.,Achab, A.,Candito, D.A.,Fradera, X.,Lesburg, C.A.,Kawamura, S.,Lacey, B.M.,Lim, J.,Methot, J.L.,Xu, Z.,Xu, H.,Smith, D.M.,Piesvaux, J.A.,Miller, J.R.,Bittinger, M.,Ranganath, S.H.,Bennett, D.J.,DiMauro, E.F.,Pasternak, A.
Discovery of Diaminopyrimidine Carboxamide HPK1 Inhibitors as Preclinical Immunotherapy Tool Compounds.
Acs Med.Chem.Lett., 12:653-661, 2021

PubMed Abstract: Hematopoietic progenitor kinase 1 (HPK1), a serine/threonine kinase, is a negative immune regulator of T cell receptor (TCR) and B cell signaling that is primarily expressed in hematopoietic cells. Accordingly, it has been reported that HPK1 loss-of-function in HPK1 kinase-dead syngeneic mouse models shows enhanced T cell signaling and cytokine production as well as tumor growth inhibition , supporting its value as an immunotherapeutic target. Herein, we present the structurally enabled discovery of novel, potent, and selective diaminopyrimidine carboxamide HPK1 inhibitors. The key discovery of a carboxamide moiety was essential for enhanced enzyme inhibitory potency and kinome selectivity as well as sustained elevation of cellular IL-2 production across a titration range in human peripheral blood mononuclear cells. The elucidation of structure-activity relationships using various pendant amino ring systems allowed for the identification of several small molecule type-I inhibitors with promising profiles.

PubMed: 33859804
DOI: 10.1021/acsmedchemlett.1c00096

実験手法

X-RAY DIFFRACTION (1.93 Å)