Abstract
Allosteric inhibitors have emerged as powerful therapeutic agents capable of overcoming resistance mutations that impair the efficacy of orthosteric inhibitors. However, resistance to allosteric inhibitors can also arise, posing a challenge to their long-term effectiveness. Mechanisms of resistance include altered inhibitor affinity and kinetics, disruption of the allosteric mechanism, changes in receptor recycling and activity, and off-target adaptations such as upregulation of drug efflux pumps or activation of compensatory signaling pathways. Furthermore, the specific mechanism of allosteric regulation induced by inhibitor binding can itself be susceptible to resistance mutations, leading to diminished efficacy. Understanding these diverse resistance mechanisms is crucial for developing strategies to counteract them. One promising approach involves the combination of both allosteric and orthosteric inhibitors, either as separate agents or as linked "bitopic" compounds, to mitigate the impact of resistance mutations. This review explores the molecular basis of resistance to allosteric inhibitors and potential strategies to overcome resistance, offering insights for the development of more resilient therapies.