Identification of Phomoxanthone A and B as Protein Tyrosine Phosphatase Inhibitors

Abstract

Phomoxanthone A and B (PXA and PXB) are xanthone dimers and isolated from the endophytic fungus Phomopsis sp. By254. The results demonstrated that PXB and PXA are noncompetitive inhibitors of SHP2 and PTP1B and competitive inhibitors of SHP1. Molecular docking studies showed that PXB and PXA interact with conserved domains of protein tyrosine phosphatases such as the β5-β6 loop, WPD loop, P loop, and Q loop. PXA and PXB could significantly inhibit the cell proliferation in MCF7 cells. Our results indicated that these two compounds do not efficiently inhibit PTP1B and SHP2 activity. RNA sequencing showed that PXA and PXB may inhibit SHP1 activity in MCF7 cells leading to the upregulation of inflammatory factors. In addition to PTP inhibition, PXA and PXB are multitarget compounds to inhibit the proliferation of tumor cells. In conclusion, both compounds show inhibition of cancer cells and a certain degree of inflammatory stimulation, which make them promising for tumor immunotherapy.

Talaromyoxaones A and B: Unusual Oxaphenalenone Spirolactones as Phosphatase Inhibitors from the Marine-Derived Fungus Talaromyces purpureogenus SCSIO 41517

“…To preliminarily understand the potential interactions between 1 and SHP1/SHP2/MEG2, human protein models 4GS0, 3MOW, and 4GE2 were used for molecular docking studies with the stereoisomer of 1 ((1 S ,6’ R ,7’ R )- 1 ). , Their potential interactions are summarized in Table S7. The binding modes were illustrated by PyMOL and Discovery Studio 2.5 software (Figures S34–S36).…”

Phomoxanthone A Targets ATP Synthase

“…Phomoxanthone A (1) is a naturally occurring dimeric tetrahydroxanthone that possesses both an enticing molecular architecture and impressive biological properties (Figure 1). [1][2][3][4][5][6][7][8][9][10] For example, phomoxanthone A is known to have antibacterial, antimalarial, and anticancer activity. It has been observed that 1 is equally as effective at killing both cisplatin sensitive and cisplatin resistant cancer cells.…”

“…[6] A separate study by Chen and Luo identified phomoxanthone A as a protein tyrosine phosphatase inhibitor. [7] However, the role of these two biomolecular targets in affecting mitochondrial disintegration is unclear leaving open the possibility of phomoxanthone A having more direct target(s) in the mitochondria. This gap in knowledge inspired us to use our synthetic experience to enable the investigation of the biomolecular targets of phomoxanthone A. Herein, we detail the identification of ATP synthase as a biomolecular target of phomoxathone A using a photoaffinity labelling approach.…”

“…Follow up studies by Monti identified carbamoyl‐phosphate synthase 1 as a possible target of phomoxanthone A [6] . A separate study by Chen and Luo identified phomoxanthone A as a protein tyrosine phosphatase inhibitor [7] . However, the role of these two biomolecular targets in affecting mitochondrial disintegration is unclear leaving open the possibility of phomoxanthone A having more direct target(s) in the mitochondria.…”

Robust, Enantioselective Construction of Challenging, Biologically Relevant Tertiary Ether Stereocenters

“…Phomoxanthone A ( 1 , Scheme ) is a naturally occurring dimeric tetrahydroxanthone with an enticing biological profile, including significant activity toward both cisplatin-sensitive and -resistant cancer cells . The impressive biological properties of phomoxanthone A have spurred investigations into its possible mode of action.…”