Abstract
Charting future innovations is challenging. Yet, allosteric and orthosteric anticancer drugs are undergoing a revolution and taxing unresolved dilemmas await. Among the imaginative innovations, here we discuss cereblon and thalidomide derivatives as a means of recruiting neosubstrates and their degradation, allosteric heterogeneous bifunctional drugs like PROTACs, drugging phosphatases, inducers of targeted posttranslational protein modifications, antibody-drug conjugates, exploiting membrane interactions to increase local concentration, stabilizing the folded state, and more. These couple with harnessing allosteric cryptic pockets whose discovery offers more options to modulate the affinity of orthosteric, active site inhibitors. Added to these are strategies to counter drug resistance through drug combinations co-targeting pathways to bypass signaling blockades. Here, we discuss on the molecular and cellular levels, such inspiring advances, provide examples of their applications, their mechanisms and rational. We start with an overview on difficult to target proteins and their properties-rarely, if ever-conceptualized before, discuss emerging innovative drugs, and proceed to the increasingly popular allosteric cryptic pockets-their advantages-and critically, issues to be aware of. We follow with drug resistance and in-depth discussion of tumor heterogeneity. Heterogeneity is a hallmark of highly aggressive cancers, the core of drug resistance unresolved challenge. We discuss potential ways to target heterogeneity by predicting it. The increase in experimental and clinical data, computed (cell-type specific) interactomes, capturing transient cryptic pockets, learned drug resistance, workings of regulatory mechanisms, heterogeneity, and resistance-based cell signaling drug combinations, assisted by AI-driven reasoning and recognition, couple with creative allosteric drug discovery, charting future innovations.