Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells perform tumour surveillance and provide a defense against viral infection and intracellular pathogens, by inducing apoptosis of virus-infected or transformed cells. A major component of this defense is the glycoprotein perforin. Upon stable conjugation of the CTL or NK cell with a target cell, perforin is released, binds calcium and assembles into aggregates of 12-18 molecules that form trans-membrane pores in the plasma membrane. This allows leakage of cell contents and the entry of secreted serine proteases (granzymes) which promote apoptosis.
Stimulation of CTL and NK cells, leading to abnormal cellular destruction, occurs in several autoimmune diseases (e.g., insulin-dependent diabetes) and in therapy-induced conditions (e.g., allograft rejection, graft-versus-host disease). In this context, small-molecule inhibitors of perforin function are of potential interest as a new class of therapeutic immunosuppressive agents.
To date, the only reported direct inhibitors of perforin function are those published by the present inventors (Lena et al, J. Med. Chem., 51(23), 7614-7624, 2008; Lyons et al, Bioorganic & Medicinal Chemistry, 19, 4091-4100, 2011; Spicer et al, Bioorganic & Medicinal Chemistry, 20, 1319-1336, 2012). Other reported inhibitors of perforin function are non-selective, complex natural products, primarily concanamycin A and other V-ATPase inhibitors such as bafilomycin A and prodigiosin 25-Cs that inhibit acidification. Other reported non-selective perforin inhibitors include cytochalasin D (an inhibitor of actin polymerisation), antimycin A and oligomycin A (inhibitors of cell respiration) and some protein kinase inhibitors (calphostin C, herbimycin A, staurosporine). However, such non-selective compounds display a broad spectrum of biological effects that generally make them undesirable for use in the treatment or prevention of conditions associated with aberrant perforin expression and/or activity.
In one or more aspects, the present invention may advantageously provide a class of compounds and their analogues as drugs for immunosuppressive therapies, or to at least provide a useful alternative to existing treatment modalities.