Exploring the Existing Drug Space for Novel pTyr Mimetic and SHP2 Inhibitors

Abstract

Protein tyrosine phosphatases (PTPs) are potential therapeutic targets for many diseases. Unfortunately, despite considerable drug discovery efforts devoted to PTPs, obtaining selective and cell permeable PTP inhibitors remains highly challenging. We describe a strategy to explore the existing drug space for previously unknown PTP inhibitory activities. This led to the discovery of cefsulodin as an inhibitor of SHP2, an oncogenic phosphatase in the PTP family. Crystal structure analysis of SHP2 interaction with cefsulodin identified sulfophenyl acetic amide (SPAA) as a novel phosphotyrosine (pTyr) mimetic. A structure-guided and SPAA fragment-based focused library approach produced several potent and selective SHP2 inhibitors. Notably, these inhibitors blocked SHP2-mediated signaling events and proliferation in several cancer cell lines. Thus, SPAA may serve as a new platform for developing chemical probes for other PTPs. KEYWORDS:Protein tyrosine phosphatase, pTyr mimetics, SHP2 inhibitors, fragment-based library, anticancer agents P roper level of protein tyrosine phosphorylation is vital for cell growth and survival. Aberrant tyrosine phosphorylation, due to imbalance of activities of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), is linked to numerous human diseases and offers enormous opportunities for therapeutic intervention. The success for such targeted approach has been well established by the more than two-dozen PTK inhibitors already used in clinic. 1 However, acquired resistance to PTK inhibitors limit durable responses. Therefore, there is great potential to modulate disease progression at the level of PTPs. To this end, the Src homology 2 (SH2) domain containing PTP2 (SHP2), encoded by the PTPN11 gene, is a positive signal transducer, required for most receptor PTKmediated Ras/ERK1/2 activation. 2,3 In addition, considerable evidence indicates that SHP2 is a bona fide oncoprotein as activating SHP2 mutations are found in leukemia and solid tumors. 4,5 Moreover, given the obligatory requirement of SHP2 in growth factor-mediated pathways, thwarting SHP2 activity may also prove effective for cancers caused by abnormal activation of receptor PTKs, some of which respond poorly to kinase inhibitor monotherapy. Hence there is strong interest in developing small molecule SHP2 inhibitors as novel anticancer agents. 6 However, the conserved PTP active site (i.e., pTyr-binding pocket) 7 makes it difficult to develop isozyme-specific inhibitors. One useful paradigm for the design of potent and selective PTP inhibitors is to engage both the active site and unique peripheral binding pockets by tethering appropriately functionalized moieties to a nonhydrolyzable pTyr mimetic. 8,9 Application of this strategy has enabled the development of a number of small molecule PTP probes. 10 Unfortunately, most existing pTyr mimetic-containing PTP inhibitors lack appropriate cellular efficacy, which represents a major obstacle in developing PTP-based therapeutics. Consequently, there is ...

Mycobacterial Protein Tyrosine Phosphatases A and B Inhibitors Augment the Bactericidal Activity of the Standard Anti-tuberculosis Regimen

“…More recently, we discovered that cefsulodin, a third generation cephalosporin β-lactam antibiotic, exhibits inhibitory activity against a number of PTPs 23 . Fragmentation analysis of cefsulodin identified α-sulfophenylacetic amide (SPAA) as an mPTP-inhibiting pharmacophore and a novel pTyr mimetic.…”

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

“…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.…”

“…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.…”

“…2H) 13. C NMR (101 MHz, chloroform-d) δ ppm 151.58, 146.66, 136.56, 136.30, 134.24, 132.13, 131.78, 131.56, 129.34, 128.32.…”

Oxidative Coupling of Aryl Boron Reagents with sp3‐Carbon Nucleophiles: The Enolate Chan–Evans–Lam Reaction

“…1,3-Phosphonyl esters (5a-c)a nd as ulfonyl ester (6a)u ndergo oxidative coupling with similar efficiencyt o1 ,3-diesters.O fn ote,e ach of these classes of compounds,m ade accessible by this copper-mediated oxidative arylation strategy,represents an important fragment in medicinal chemistry,s uch as in blactam antibiotics,t yrosine phosphatase inhibitors,a nd histone deacetylase inhibitors. [25] …”