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- Title
Targeting SHP2 Cryptic Allosteric Sites for Effective Cancer Therapy.
- Authors
Rehman, Ashfaq Ur; Zhao, Cizhang; Wu, Yongxian; Zhu, Qiang; Luo, Ray
- Abstract
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.
- Subjects
CANCER treatment; LIGANDS (Biochemistry); COMPUTATIONAL chemistry; PROTEIN-tyrosine phosphatase; BINDING sites; LIGAND binding (Biochemistry)
- Publication
International Journal of Molecular Sciences, 2024, Vol 25, Issue 11, p6201
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms25116201