Shp2 protein tyrosine phosphatase inhibitor activity of estramustine phosphate and its triterpenoid analogs

Abstract

Shp2 protein tyrosine phosphate (PTP) is a novel target for anticancer drug discovery. We identified estramustine phosphate as a Shp2 PTP inhibitor from the National Cancer Institute Approved Oncology Drug set. A focused structure-activity relationship study indicated that the 17-phosphate group is required for the Shp2 PTP inhibitor activity of estramustine phosphate. A search for estramustine phosphate analogs led to identification of two triperpenoids, enoxolone and celastrol, having Shp2 PTP inhibitor activity. With the previously reported PTP1B inhibitor trodusquemine, our study reveals steroids and triterpenoids with negatively charged phosphate, carboxylate, or sulfonate groups as novel pharmacophores of selective PTP inhibitors. KeywordsShp2; Protein tyrosine phosphatase; Estramustine phosphate; Enoxolone; Celastrol; Triterpenoids Protein tyrosine phosphorylation is a major signaling mechanism that controls cellular activities pertinent to cancer initiation and progression. Protein tyrosine phosphorylation is coordinately regulated by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). While many PTKs have well-demonstrated roles in human cancer and are validated targets of anticancer drugs, increasing evidence also shows that a number of PTPs, such as

New structural and functional insight into the regulation of Ras

“…Although the direct relationship between Ras and Shp2 has remained unclear, the ubiquitous tyrosine phosphatase Shp2 has been shown to have a pivotal role in the activation of the Ras/MAPK pathway [69]. Recently, Shp2 was shown to dephosphorylate and activate Ras [70].…”

“…Furthermore, ubiquitously expressed tyrosine phosphatase Shp2 has also emerged as a major regulator of the Ras/MAPK signaling pathway [15]. Germline activating mutations in Shp2 cause Noonan syndrome, whereas somatic gain of function Shp2 mutations have been identified in several haematologic malignancies, most notably juvenile myelomonocytic leukaemia.…”

Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases

“…Although catalytic SHP2 inhibitors have been described [11][12][13][14][15] , they are typically of low potency and inhibit other phosphatases. Although the allosteric inhibition of a metaldependent serine/threonine phosphatase family has been explored 21 , SHP099 is the first example of a potent, selective and orally bioavailable allosteric PTP inhibitor specific to SHP2 that is efficacious and well tolerated in patient-derived tumour xenograft models.…”

“…1b). These data strongly suggest that cancer cells carrying oncogenic RAS/RAF mutations will be refractory to SHP2 inhibition.Efforts to discover small molecule therapeutics targeting protein tyrosine phosphatases (PTPs) have been challenged by the highly solvated and polar nature of the catalytic site, as exemplified by the SHP2 PTP domain [11][12][13][14][15] . To discover novel modes of phosphatase inhibition, we developed screening strategies aimed at identifying SHP2 allosteric inhibitors.…”

Drug resistance profiles of mutations in the RET kinase domain

“…The in vitro kinase assay was performed as a commercial service by Reaction Biology (Malvern, PA) in parallel 10-dose IC50 singlet assay, with 3-fold serial dilution starting at 10 μM. Curve fitting was as described (Scott et al, 2011). Figure S4 Immunoblot analysis of pRET in BaF3/KR, BaF3/KR (V871I), and BaF3/KR (F998V) cells after TKI treatment.…”