Small molecule tools for functional interrogation of protein tyrosine phosphatases

Abstract

The importance of protein tyrosine phosphatases (PTPs) in the regulation of cellular signalling is well established. Malfunction of PTP activity is also known to be associated with cancer, metabolic syndromes and autoimmune disorders, as well as neurodegenerative and infectious diseases. However, a detailed understanding of the roles played by the PTPs in normal physiology and in pathogenic conditions has been hampered by the absence of PTP-specific small molecule agents. In addition, the therapeutic benefits of modulating this target class are underexplored as a result of a lack of suitable chemical probes. Potent and specific PTP inhibitors could significantly facilitate functional analysis of the PTPs in complex cellular signal transduction pathways and may constitute valuable therapeutics in the treatment of several human diseases. We highlight the current challenges to and opportunities for developing PTP-specific small molecule agents. We also review available selective small molecule inhibitors developed for a number of PTPs, including PTP1B, TC-PTP, SHP2, lymphoid-specific tyrosine phosphatase, haematopoietic protein tyrosine phosphatase, CD45, PTPβ, PTPγ, PTPRO, Vaccinia H1-related phosphatase, mitogen-activated protein kinase phosphatase-1, mitogen-activated protein kinase phosphatase-3, Cdc25, YopH, mPTPA and mPTPB.

Figure 1

PTP1B inhibitors.

Figure 2

TC-PTP inhibitor.

Figure 3

SHP2 inhibitors.

Figure 4

Lyp inhibitors.

Figure 5

HePTP inhibitors.

Figure 6

CD45 inhibitors.

Figure 7

PTPβ inhibitors.

Figure 8

PTPγ inhibitor.

Figure 9

PTPRO inhibitors.

Figure 10

VHR inhibitors.

Figure 11

Inhibitors of MKP-1 (compounds 33 and 34) and MKP-3 (compound 35).

Figure 12

Cdc25 inhibitors.

Figure 13

Inhibitors of YopH (compounds 39 and 40), mPTPA (compound 41), and mPTPB (compounds 42–48).