Mathematical model parameters.

<p>Mathematical model parameters.</p

Mathematical model validation.

<p>(A) The experimentally imposed increases of food intake during controlled over-feeding experiments (black bars) along with model predicted values (white bars) calculated using the measured body weight changes. (B) Model predicted relationship between changes of 24 hour energy expenditure and body weight change after 3.6 years of over- and under-feeding (♦) along with the best-fit regression line determined from longitudinal measurements in a cohort of Pima Indians followed for the same average time interval. (mean±SD).</p

Optimization of Fused Bicyclic Allosteric SHP2 Inhibitors

SHP2 is a nonreceptor protein tyrosine phosphatase within the mitogen-activated protein kinase (MAPK) pathway controlling cell growth, differentiation, and oncogenic transformation. SHP2 also participates in the programed cell death pathway (PD-1/PD-L1) governing immune surveillance. Small-molecule inhibition of SHP2 has been widely investigated, including in our previous reports describing SHP099 (2), which binds to a tunnel-like allosteric binding site. To broaden our approach to allosteric inhibition of SHP2, we conducted additional hit finding, evaluation, and structure-based scaffold morphing. These studies, reported here in the first of two papers, led to the identification of multiple 5,6-fused bicyclic scaffolds that bind to the same allosteric tunnel as 2. We demonstrate the structural diversity permitted by the tunnel pharmacophore and culminated in the identification of pyrazolopyrimidinones (e.g., SHP389, 1) that modulate MAPK signaling in vivo. These studies also served as the basis for further scaffold morphing and optimization, detailed in the following manuscript