To combat multidrug resistance (MDR) in cancer, medicinal chemists employ several key strategies. First, efflux pump evasion involves designing drug molecules that avoid recognition by P-glycoprotein (P-gp) and other ABC transporters—this can be achieved by optimizing molecular weight (

In other to fight the multidrug resistance (MDR) obstacle presented by drug-resistant cancer cells, medicinal chemists have embarked on an innovative trajectory, recognizing the active efflux of chemotherapeutic agents by ATP-binding cassette transporters, mainly P-glycoprotein (P-gp), as a prevalent mechanism driving MDR. This efflux enforces a reduction in intracellular drug concentration, hence weakening chemotherapy effectiveness and leading to treatment failure and tumor relapse. Therefore, researchers are increasingly focusing on engineering drug molecules that show minimal recognition and appropriation by these chemoresistance-related efflux pumps. Augmenting the molecular rigidity and hindering hydrogen bonding can accomplish variations in the compounds' lipophilicity, and these modifications can, in turn, reduce the efflux pump's recognition (Danhier, et al., 2010).

The drug's internal concentration, cytotoxicity, and retention in cancer cells can hence be enhanced, mitigating the tumor's resistance to chemotherapy (Szakács et al., 2006). These design strategies have been beneficial when developing novel taxanes and other chemotherapeutic options, demonstrating considerably augmented efficacy in combating resistant tumors. Designing versatile medicinal agents is another promising avenue: those that not only present strong cytotoxicity but also boast the capability to inhibit efflux pumps. In the past, the primary issue has been the substantial toxicities associated with early-generation P-gp inhibitors and the unexpected drug-drug interactions. Nonetheless, modern advancements have generated compounds that can selectively hinder the functioning of the transporters while maintaining minimal adverse effects. Furthermore, it is increasingly common to target multiple resistance pathways concurrently, thereby decreasing the chances of resistance development and augmenting the therapeutic effects of counter-MDR chemotherapeutics (Robey et al., 2018).

Targeting cellular pathways that are conventional and thus more prone to drug resistance is yet another promising tactic. Chemoresistance can be bypassed by these pathways, including apoptosis modulation, epigenetic control, and vital signaling kinases, and novel treatments can be generated as a consequence. For instance, apoptotic signaling has been reestablished with success in chemoresistant tumor cells through the use of BH3 mimetics, while kinase inhibitors can work independently on efflux pumps (Holohan et al., 2013). Thorough non-classical cellular pathway targeting ensures delivering effective anti-cancer treatment by allowing traces to steer clear of efflux-mediated drug elimination. Delivering anti-cancer medications, a tactic that can be quite advantageous, has seen significant enhancements. Finally, chemists have begun to address multidrug resistance by pursuing novel drug delivery techniques. With tumors activated within the tumor microenvironment, selective toxicity is improved while susceptibility to efflux is lessened (Szakács et al., 2006).

Offering a somewhat more efficient approach compared to diffusion, systems like nanoparticles, liposomes, and polymeric carriers can help chemotherapeutics enter cells, thereby evading the efflux pumps. Lastly, these methodologies have tremendously accelerated the drug discovery process, improving the ability to design drugs unrecognizable by efflux pumps (Wen & Zhang, 2019). In summary, the resistance to multidrug cancer treatments using medicinal chemistry has been committed to a comprehensive paradigm, which is mostly about evading efflux pumps, developing compounds that inspire double actions, targeting diverse cellular pathways, establishing technologies for novel drug deliveries, and computationally deciding the desirable design. As mentioned above, collectively taking these approaches is rather crucial to attempt to revert the present insensitivity of chemotherapy within cancer cells.

References:

Danhier, F., Feron, O., & Préat, V. (2010). To exploit the tumor microenvironment: Passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. Journal of Controlled Release, 148(2), 135-146.

Holohan, C., Van Schaeybroeck, S., Longley, D. B., & Johnston, P. G. (2013). Cancer drug resistance: An evolving paradigm. Nature Reviews Cancer, 13(10), 714-726.

Robey, R. W., Pluchino, K. M., Hall, M. D., Fojo, A. T., Bates, S. E., & Gottesman, M. M. (2018). Revisiting the role of ABC transporters in multidrug-resistant cancer. Nature Reviews Cancer, 18(7), 452-464.

Szakács, G., Paterson, J. K., Ludwig, J. A., Booth-Genthe, C., & Gottesman, M. M. (2006). Targeting multidrug resistance in cancer. Nature Reviews Drug Discovery, 5(3), 219-234.

Cancer cells live in an environment with low pH and low oxygen levels, so we create a pro-We develop a drug that only works in the environment of cancer cells and create a molecule that acts on two important pathways simultaneously, so the cell cannot find a way to escape. We design a drug that binds to a different site or breaks down the entire protein (like PROTAC).