Scaffold-based selective SHP2 inhibitors design using core hopping, molecular docking, biological evaluation and...

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Molecular Biology

Background:

• PTPN11 encodes SHP2, a protein tyrosine phosphatase crucial in cell signaling.
• Abnormal SHP2 activation is linked to diseases like JMML, Noonan syndrome, and various cancers.
• SHP2 inhibitors hold significant therapeutic potential for treating these conditions.

Purpose of the Study:

• To discover novel and efficient inhibitors of SHP2.
• To identify potent thiophene [2,3-d] pyrimidine derivatives as SHP2 inhibitors.
• To investigate the molecular mechanism of action for the most active inhibitor.

Main Methods:

• Utilized "core hopping" and CDOCKER technology for inhibitor discovery.
• Performed SHP2-PTP phosphatase activity assays to determine inhibitor potency.
• Employed molecular dynamics (MD) simulation and post-kinetic analysis to study inhibitor-protein interactions.

Main Results:

• Discovered thiophene [2,3-d] pyrimidine derivatives with IC50 values ranging from 0.4-37.87 μM.
• Identified Comp#5 as the most potent SHP2 inhibitor with an IC50 of 0.4 μM.
• MD simulations revealed Comp#5 enhances catalytic active region stability and selectivity by interacting with key residues like ARG362.

Conclusions:

• Thiophene [2,3-d] pyrimidine derivatives represent a promising class of novel SHP2 inhibitors.
• Comp#5 exhibits potent inhibitory activity and favorable interactions with SHP2.
• This research may facilitate the development of new SHP2-targeted cancer therapies.