Screening of tyrosine phosphatase SHP2 (PTPN11) inhibitors from natural products with therapeutic potential for receptor tyrosine kinase-driven cancer.

Src homology 2 domain-containing phosphatase 2 (SHP2) is a pivotal regulator linking receptor tyrosine kinase (RTK) signaling. Abnormal SHP2 activity has been associated with tumorigenesis and metastasis. Although some SHP2-targeting modulators have entered clinical trials, U.S. Food and Drug Administraction (FDA)-approved SHP2 targeting drugs are still not available. Herein, we describe cooperative biochemical inhibition experiments that facilitate the identification of both catalytic and allosteric SHP2 inhibitors using an in-house natural product (NP) library. Based on this screening methodology, structurally diverse sets of NPs were characterized, among which dihydrotanshinone I (DHT) potently inhibited the wild-type SHP2 protein tyrosine phosphatase (PTP) domain and gain-of-function SHP2 variants. Trichostatin A (TSA) bound to the "tunnel" binding site, acting as an allosteric inhibitor. This study illustrates an optimized screening methodology and tactics to identify novel SHP2 modulators from NPs and provides a foundation for further NP-based drug development for the treatment of RTK-driven cancer.