8RZY

A fragment-based inhibitor of SHP2

This is a non-PDB format compatible entry.

Summary for 8RZY

• Entry DOI: 10.2210/pdb8rzy/pdb
• Descriptor: Tyrosine-protein phosphatase non-receptor type 11, 1H-pyrrolo[3,2-b]pyridin-5-amine, DIMETHYL SULFOXIDE, ... (4 entities in total)
• Functional Keywords: protein tyrosine phophatase, sh2 domain, autoinhibition, allostery, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 124144.01

Authors

Cleasby, A.,Price, A. (deposition date: 2024-02-13, release date: 2024-03-20, Last modification date: 2024-04-10)

Primary citation

Day, J.E.H.,Berdini, V.,Castro, J.,Chessari, G.,Davies, T.G.,Day, P.J.,St Denis, J.D.,Fujiwara, H.,Fukaya, S.,Hamlett, C.C.F.,Hearn, K.,Hiscock, S.D.,Holvey, R.S.,Ito, S.,Kandola, N.,Kodama, Y.,Liebeschuetz, J.W.,Martins, V.,Matsuo, K.,Mortenson, P.N.,Muench, S.,Nakatsuru, Y.,Ochiiwa, H.,Palmer, N.,Peakman, T.,Price, A.,Reader, M.,Rees, D.C.,Rich, S.J.,Shah, A.,Shibata, Y.,Smyth, T.,Twigg, D.G.,Wallis, N.G.,Williams, G.,Wilsher, N.E.,Woodhead, A.,Shimamura, T.,Johnson, C.N.
Fragment-Based Discovery of Allosteric Inhibitors of SH2 Domain-Containing Protein Tyrosine Phosphatase-2 (SHP2).
J.Med.Chem., 67:4655-4675, 2024

PubMed Abstract: The ubiquitously expressed protein tyrosine phosphatase SHP2 is required for signaling downstream of receptor tyrosine kinases (RTKs) and plays a role in regulating many cellular processes. Genetic knockdown and pharmacological inhibition of SHP2 suppresses RAS/MAPK signaling and inhibit the proliferation of RTK-driven cancer cell lines. Here, we describe the first reported fragment-to-lead campaign against SHP2, where X-ray crystallography and biophysical techniques were used to identify fragments binding to multiple sites on SHP2. Structure-guided optimization, including several computational methods, led to the discovery of two structurally distinct series of SHP2 inhibitors binding to the previously reported allosteric tunnel binding site (Tunnel Site). One of these series was advanced to a low-nanomolar lead that inhibited tumor growth when dosed orally to mice bearing HCC827 xenografts. Furthermore, a third series of SHP2 inhibitors was discovered binding to a previously unreported site, lying at the interface of the C-terminal SH2 and catalytic domains.

PubMed: 38462716
DOI: 10.1021/acs.jmedchem.3c02118

Experimental method

X-RAY DIFFRACTION (1.91 Å)