29CY

Fragment-based covalent targeting of lysines at the allosteric latch site of SHP2

Summary for 29CY

• Entry DOI: 10.2210/pdb29cy/pdb
• Descriptor: Tyrosine-protein phosphatase non-receptor type 11, 1,2-ETHANEDIOL, 1-(3-chloro-4-{[1-(2-hydroxy-3-methoxyphenyl)-5-oxo[1,2,4]triazolo[4,3-a]quinazolin-4(5H)-yl]methyl}benzene-1-carbonyl)-L-proline, ... (4 entities in total)
• Functional Keywords: covalent shp2 inhibitors, allosteric latch site, compound 26, cytosolic protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 122552.81

Authors

Roske, Y.,Daumke, O.,Keseru, M.,Abranyi-Balogh, P. (deposition date: 2026-03-06, release date: 2026-10-21, Last modification date: 2026-11-04)

Primary citation

Di Lorenzo, V.,Csorba, N.,Szabo, R.,Kollar, L.,Roske, Y.,Randelovic, I.,Balazs, K.,Szalai, T.V.,Efrem, N.L.,Mihalovits, L.,Imre, T.,Simon, J.,Tovari, J.,Nazare, M.,Daumke, O.,Abranyi-Balogh, P.,Keseru, G.M.
Fragment-Based Covalent Targeting of Lysines at the Allosteric Latch Site of SHP2.
J.Med.Chem., 69:21955-21971, 2026

PubMed Abstract: Covalent mechanism of action is a powerful way to modulate challenging drug targets. Here, we present a streamlined workflow that combines covalent fragment screening (electrophile first approach) and ligand-first strategy to identify covalent inhibitors targeting lysine residues in the allosteric latch site of SHP2 phosphatase. Supported by complementary computational and experimental analyses, this strategy enabled us to identify the first potent cell active allosteric covalent inhibitors acting at this site. Demonstrating the covalent tractability of the latch site opens further avenues for future optimization and therapeutic exploration of high-value allosteric SHP2 inhibitors.

PubMed: 42917893
DOI: 10.1021/acs.jmedchem.6c01030

Experimental method

X-RAY DIFFRACTION (2.63 Å)