SHP2 (PTPN11) is a protein tyrosine phosphatase (PTP) containing two Src homology-2 domains (N-SH2, C-SH2), a PTP domain, and a carboxyl-terminal region [1]. SHP2 is auto-inhibited by the N-SH2 domain and PTP domain interaction in the basal state. In cancer cells, SHP2 is activated by oncogenic protein tyrosine kinases (PTKs) or gainof-function (GOF) mutations. GOF SHP2 mutations also link to Noonan Syndrome (NS)[2].

SHP2 plays important roles in tumor growth [3, 4], in oncogenesis driven by PTK oncogenes such as FLT3-ITD in acute myeloid leukemia [5], and in immune checkpoints mediated by PD-1 or BTLA [6]. GOF SHP2 mutations are found in leukemias, particularly juvenile myelomonocytic leukemia (JMML), and in solid tumors [1]. SHP2 has been targeted for cancer drug discovery [7, 8]. However, it is challenging to develop potent, selective, and cell-permeable SHP2 inhibitors targeting the PTP catalytic site. Recently, a novel allosteric SHP2 inhibitor (SHP099) was identified [9, 10]. SHP099 binds to a tunnel-like area comprised of all three domains in SHP2 (Fig. 1a), and stabilizes it in an inactive conformation. Several leukemia cell lines expressing PTK driver oncogenes, such as FLT3-ITD and PDGFRA, were the most sensitive to SHP099 (IC50< 10µM)[10]. However, it was unclear whether SHP099 inhibits SHP2 mutants. We synthesized SHP099 and tested it in the MV4-11 myeloid leukemia cells [10]. SHP099 potently inhibited MV4-11 cell growth (IC50: 0.32±0.11 µM; Supplementary Figure 1a), reduced pERK1/2 and Bcl-XL levels, and induced PARP cleavage (Supplementary Figure 1b). Thus, SHP099 synthesized by us had activity similar to that reported [10].