Though natural product compounds, like cyclosporin a, have demonstrated for decades that cyclic peptides can balance drug-like properties and challenging target engagement; achieving the same in synthetic systems has proved very challenging. Herein we report the use of <i>in silico</i> design and parallel synthesis to achieve passive cell permeability in a MW&gt;1000Da compound series. These compounds potently and selectively reactivate wt-p53 by inhibiting their negative regulators MDM2 & MDM4(X) in cellular and<i> in vivo. </i>This compound series demonstrates that the purely synthetic peptides, well beyond the Lipinski space, can achieve passive cell permeability while engaging high-value intracellular targets in a designed, and repeatable manner.

Aggressively passive: Achieving truly small-molecule-like properties in bRo5 macrocyclic peptides.

ACS Spring Meeting 2021

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