Identification and signaling characterization of GNASR201H/C selective inhibitors for FD/MAS

Awardee: Edward Hsiao

Co-PI: Kelly Wentworth

Institution: University of California, San Francisco

Grant Amount: $53,791

Funding Period: February 1, 2022 - January 31, 2023

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Summary:

Fibrous dysplasia and McCune Albright syndrome (FD/MAS) are severe congenital conditions caused by activating point mutations in the GNAS gene; however, specific molecular tools for directly perturbing GNAS activity in a mutation specific fashion are largely lacking. The overall goal of this proposal is to complete the analysis of a series of promising compounds that we previously identified as likely to specifically bind GNASR201H. We will use a novel human induced pluripotent stem cell model carrying the GNASR201H mutation in the endogenous locus to test our top drug candidates for their ability to block the abnormal cAMP production, and also use physical assays to determine if the inhibition occurs through direct binding to GNAS or by acting on a downstream pathway component. This proposal directly addresses critical needs by identifying promising molecular tools for dissecting GNASR201H function and serving as scaffolds for developing novel therapeutics that directly target GNAS mutations that cause FD/MAS, and validating a new human IPS cell model that will be useful for studies of cellular differentiation and function in FD/MAS. All reagents, compounds, cell lines, and analytical methods are already available through the collaborators and experienced team.