Targeting SHP2 Cryptic Allosteric Sites for Effective Cancer Therapy

• Published in: International journal of molecular sciences Vol. 25; no. 11; p. 6201
• Main Authors: Rehman, Ashfaq Ur, Zhao, Cizhang, Wu, Yongxian, Zhu, Qiang, Luo, Ray
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.06.2024; MDPI
• Subjects: Allosteric Regulation - drug effects; Allosteric Site; Analysis; Antimitotic agents; Antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Binding Sites; Cancer; Care and treatment; Cell growth; Development and progression; Enzymes; Flexibility; Health aspects; Humans; Investigations; Kinases; Leukemia; Ligands; Molecular Dynamics Simulation; Mutation; Neoplasms - drug therapy; Neoplasms - metabolism; NMR; Nuclear magnetic resonance; Phosphatase; Protein Binding; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - chemistry; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism; Proteins; Simulation; Simulation methods; Tumors; Tyrosine; computational chemistry; molecular dynamics; protein tyrosine phosphatase; structure dynamics; multi-scale docking
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25116201

SHP2, a pivotal component downstream of both receptor and non-receptor tyrosine kinases, has been underscored in the progression of various human cancers and neurodevelopmental disorders. Allosteric inhibitors have been proposed to regulate its autoinhibition. However, oncogenic mutations, such as E76K, convert SHP2 into its open state, wherein the catalytic cleft becomes fully exposed to its ligands. This study elucidates the dynamic properties of SHP2 structures across different states, with a focus on the effects of oncogenic mutation on two known binding sites of allosteric inhibitors. Through extensive modeling and simulations, we further identified an alternative allosteric binding pocket in solution structures. Additional analysis provides insights into the dynamics and stability of the potential site. In addition, multi-tier screening was deployed to identify potential binders targeting the potential site. Our efforts to identify a new allosteric site contribute to community-wide initiatives developing therapies using multiple allosteric inhibitors to target distinct pockets on SHP2, in the hope of potentially inhibiting or slowing tumor growth associated with SHP2.