4.6 Article

Discovery of novel furanylbenzamide inhibitors that target oncogenic tyrosine phosphatase SHP2 in leukemia cells

Journal

JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 298, Issue 1, Pages -

Publisher

ELSEVIER
DOI: 10.1016/j.jbc.2021.101477

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Funding

  1. National Cancer Institute (NCI) of the National Institutes of Health [1R21CA195422, 1R21NS067502]
  2. NCI Cancer Center support grant [P30CA030199]
  3. Epstein Family Foundation
  4. NCI, National Institutes of Health, under Chemical Biology Consortium [HHSN261200800001E]

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Disturbance of the balance between tyrosine phosphorylation and dephosphorylation controlled by protein tyrosine kinases and protein tyrosine phosphatases (PTPs) can lead to cancer development. PTPs, which have long been considered undruggable, are now gaining attention in drug discovery. One PTP target is SHP2, which is involved in tumor initiation, progression, metastasis, and treatment resistance. This study reports the discovery of novel furanylbenzamide molecules as inhibitors of both WT and oncogenic SHP2, showing potential as therapeutic targets for cancer treatment.
Disturbance of the dynamic balance between tyrosine phosphorylation and dephosphorylation of signaling molecules, controlled by protein tyrosine kinases and protein tyrosine phosphatases (PTPs), is known to lead to the development of cancer. While most approved targeted cancer therapies are tyrosine kinase inhibitors, PTPs have long been stigmatized as undruggable and have only recently gained renewed attention in drug discovery. One PTP target is the Src-homology 2 domain-containing phosphatase 2 (SHP2). SHP2 is implicated in tumor initiation, progression, metastasis, and treatment resistance, primarily because of its role as a signaling nexus of the extracellular signal-regulated kinase pathway, acting upstream of the small GTPase Ras. Efforts to develop small molecules that target SHP2 are ongoing, and several SHP2 allosteric inhibitors are currently in clinical trials for the treatment of solid tumors. However, while the reported allosteric inhibitors are highly effective against cells expressing WT SHP2, none have significant activity against the most frequent oncogenic SHP2 variants that drive leukemogenesis in several juvenile and acute leukemias. Here, we report the discovery of novel furanylbenzamide molecules as inhibitors of both WT and oncogenic SHP2. Importantly, these inhibitors readily cross cell membranes, bind and inhibit SHP2 under physiological conditions, and effectively decrease the growth of cancer cells, including triple-negative breast cancer cells, acute myeloid leukemia cells expressing either WT or oncogenic SHP2, and patient-derived acute myeloid leukemia cells. These novel compounds are effective chemical probes of active SHP2 and may serve as starting points for therapeutics targeting WT or mutant SHP2 in cancer.

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