9D00

HPK1 kinase domain T165E,S171E phosphomimetic mutant in complex with compound 53

これはPDB形式変換不可エントリーです。

9D00 の概要

• エントリーDOI: 10.2210/pdb9d00/pdb
• 関連するPDBエントリー: 9CZT 9CZU 9CZW 9CZX
• 分子名称: Mitogen-activated protein kinase kinase kinase kinase 1, 4-[(1R)-1-aminopropyl]-6-methoxy-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3-yl]pyridin-2-yl}-2,3-dihydro-1H-isoindol-1-one (3 entities in total)
• 機能のキーワード: kinase, 3d domain swap, inactive state, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 139645.47

構造登録者

Johnson, E.,McTigue, M.,Cronin, C.N. (登録日: 2024-08-05, 公開日: 2024-12-18, 最終更新日: 2025-01-08)

主引用文献

Gallego, R.A.,Cho-Schultz, S.,Del Bel, M.,Dechert-Schmitt, A.M.,Donaldson, J.S.,He, M.,Jalaie, M.,Kania, R.,Matthews, J.,McTigue, M.,Tuttle, J.B.,Risley, H.,Zhou, D.,Zhou, R.,Ahmad, O.K.,Bernier, L.,Berritt, S.,Braganza, J.,Chen, Z.,Cianfrogna, J.A.,Collins, M.,Costa Jones, C.,Cronin, C.N.,Davis, C.,Dress, K.,Edwards, M.,Farrell, W.,France, S.P.,Grable, N.,Johnson, E.,Johnson, T.W.,Jones, R.,Knauber, T.,Lafontaine, J.,Loach, R.P.,Maestre, M.,Miller, N.,Moen, M.,Monfette, S.,Morse, P.,Nager, A.R.,Niosi, M.,Richardson, P.,Rohner, A.K.,Sach, N.W.,Timofeevski, S.,Tucker, J.W.,Vetelino, B.,Zhang, L.,Nair, S.K.
Discovery of PF-07265028, A Selective Small Molecule Inhibitor of Hematopoietic Progenitor Kinase 1 (HPK1) for the Treatment of Cancer.
J.Med.Chem., 67:22002-22038, 2024

PubMed Abstract: Hematopoietic progenitor kinase 1 (HPK1/MAP4K1) represents a high interest target for the treatment of cancer through an immune-mediated mechanism. Herein we present highlights of the drug discovery campaign within the lactam/azalactam series of inhibitors that yielded a small molecule (, PF-07265028), which was advanced to a phase 1 clinical trial (NCT05233436). Key components of the discovery effort included optimization of potency through mitigation of ligand strain as guided by the use of cocrystal structures, mitigation of ADME liabilities (plasma instability and fraction metabolism by CYP2D6), and optimization of kinase selectivity, particularly over immune-modulating kinases with high homology to HPK1. Structure-based drug design via leveraging cocrystal structures and lipophilic efficiency analysis proved to be valuable tools that ultimately enabled the delivery of a clinical-quality small molecule inhibitor of HPK1.

PubMed: 39651809
DOI: 10.1021/acs.jmedchem.4c01930

実験手法

X-RAY DIFFRACTION (1.951 Å)