The Src homology-2 domain-containing phosphatase 2 (SHP2), encoded by PTPN11, is a central node in RAS signaling and cancer and a pivotal target for anticancer therapy. PTPN11 mutations cause ~35% of cases of juvenile myelomonocytic leukemia (JMML) and occur in other malignancies. In addition, SHP2 is required for survival of RTK-driven cancer cells, contributes to resistance to anti-cancer drugs and modulates immune checkpoints.
SHP2 comprises a catalytic PTP domain, and two SH2 domains (N-SH2 and C-SH2) mediating its interaction with phosphotyrosine-containing binding partners. Under basal conditions, the N-SH2 domain blocks the PTP active site and SHP2 is inactive. Most pathogenic mutations perturb this autoinhibited structure, enhancing basal phosphatase activity, simultaneously causing an increase in N-SH2 affinity for binding partners, through an allosteric mechanism. Several lines of evidence indicate that the latter effect is the main driver of RAS pathway hyperactivation caused by PTPN11 mutations.
In this seminar I will illustrate our current structural and dynamical knowledge of the allosteric mechanism of SHP2 regulation. In addition, I will present a new class of inhibitors of SHP2 protein−protein interactions. Currently available SHP2 inhibitors target the catalytic site or an allosteric pocket but lack specificity or are ineffective on disease-associated SHP2 mutants. Considering that pathogenic lesions cause signaling hyperactivation due to increased levels of SHP2 association with cognate proteins, we developed peptide-based molecules with nanomolar affinity for the N-terminal Src homology domain of SHP2, good selectivity, stability to degradation, and an affinity for pathogenic variants of SHP2 that is 2−20 times higher than for the wild-type protein. The best peptide reverted the effects of a pathogenic variant in zebrafish embryos. Efforts to additionally improve the pharmacological properties of these inhibitors, to optimize their intracellular delivery and to explore other molecules with a similar mechanism of action are currently underway.
Our results provide a novel route for SHP2-targeted therapies and a tool for investigating the role of protein−protein interactions in the function of SHP2.
5 Maggio 2023
Prof. Lorenzo Stella
Dipartimento di Scienze e Tecnologie Chimiche
Università di Roma “Tor Vergata”
stella@stc.uniroma2.it
Aula A CU010
ore 13:00