Mutations in the protein tyrosine phosphatase (PTP) Src-homology-2-domain-containing PTP-2 (SHP2) cause Noonan and LEOPARD syndromes and are the most common cause of sporadic juvenile myelomonocytic leukemia. Moreover, SHP2 activity has been strongly implicated in oncogenesis even in instances in which the enzyme does not itself harbor mutations. SHP2 inhibitors may therefore represent important therapeutics for both cancer and developmental disorders. However, active-site-directed SHP2 inhibitors have generally not proven to be highly effective in a cellular context. We are developing allosteric SHP2 inhibitors that target non-active-site, non-conserved cysteine residues for potent, covalent, and selective SHP2 inhibition. Specifically, we will describe efforts toward the identification of compounds that interact with three cysteine residues of SHP2: one that occurs in the wild-type enzyme (C333) and two that are found only in disease-causing SHP2 mutants (C63, Noonan syndrome and C279, LEOPARD syndrome). C333 lies in a recently discovered PTP-domain allosteric site, in a position occupied by proline in most PTPs, providing an opportunity for selective electrophilic engagement of wild-type SHP2. C63 and C279 are disease-causing cysteine mutations that alter SHP2’s PTP activity and appear in no other PTPs. Compounds that target C63 or C279 are therefore potentially capable of selectively blocking the activity of the aberrant enzymes. Collectively, our studies provide the first examples of selective PTP inhibition through engagement of targeting non-conserved cysteines and may have direct implications for SHP2-targeted drug development.

Targeting non-conserved cysteines for allosteric inhibition of SHP2

2019 Fall National Meeting

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