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Covalent/irreversible inhibitors target the redox/catalytic apparatus of TGR with almost no recognition elements that give affinity and selectivity for TGR over off-targets and the cellular redox apparatus resulting in undesirable cross-reactions and low specificity in vivo 25

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Fourthly, cross-resistance, where exposure to a single therapeutic pressure activates underlying anti-apoptotic pathways, leading to spontaneous resistance to heterogeneous therapies not previously encountered [17, 18]

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