A Potent and Specific Inhibitor of Lipid–SH2 Domain Interactions Was Developed

Despite the critical role of lipid–protein interactions (LPI) in cellular signaling, drug discovery targeting these interactions has proven challenging. In an effort to develop a new class of specific and potent LPI inhibitors, Singaram, Sharma, and colleagues sought to target the lipid binding of Src homology 2 (SH2) domains, using spleen tyro­sine kinase (Syk) as a model, as most non-receptor tyrosine kinases contain lipid-binding SH2 domains. Computational and biophysical studies indicated that the C-terminal SH2 domain of Syk (Syk-cSH2) specifically interacts with PIP₃ phosphate moieties and that this interaction may be inhibited by nonlipid-like small molecules. High-throughput molecular docking and computational analyses were used to construct a 600 molecular library of potential LPI inhibitors of Syk-cSH2, and lead compounds were optimized for inhibitory activity leading to identification of WC36. WC36 specifically blocked the Syk-cSH2–PIP₃ interaction, which plays a critical role in plasma membrane recruitment and activation of Syk in immune cell receptor signaling and had less off-target toxicity as compared to Syk ATP-competitive inhibitors, such as entospletinib. Assessment of the efficacy of this Syk LPI inhibitor in acute myeloid leukemia (AML) cells revealed reduction in the phosphorylation of Syk as well as STAT3/5 and ERK1/2, supporting that the potency of these compounds is similar to that of entospletinib. Unlike entospletinib, however, WC36 was subject to neither de novo nor acquired resistance in AML cells. WC36 was also effective in suppressing downstream signaling in entospletinib-resistant AML cells. The lack of acquired drug resistance observed with WC36 treatment was attributed to its ability to block both Syk kinase function as well as its noncatalytic scaffolding function. Overall, this study demonstrates a new, generally applicable approach to the targeting of lipid-binding sites, specifically of SH2 domains of a wide variety of non-receptor tyrosine kinases, with its successful use being indicated through the identification of the Syk inhibitor WC36.

Singaram I, Sharma A, Pant S, Lihan M, Park MJ, Pergande M, et al. Targeting lipid–protein interaction to treat Syk-mediated acute myeloid leukemia. Nat Chem Biol 2022 Oct 13 [Epub ahead of print].

Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.