Synthetic Lethality through the Lens of Medicinal Chemistry

Personalized medicine and therapies
represent the goal of modern
medicine, as drug discovery strives to move away from one-cure-for-all
and makes use of the various targets and biomarkers within differing
disease areas. This approach, especially in oncology, is often undermined
when the cells make use of alternative survival pathways. As such,
acquired resistance is unfortunately common. In order to combat this
phenomenon, synthetic lethality is being investigated, making use
of existing genetic fragilities within the cancer cell. This Perspective
highlights exciting targets within synthetic lethality, (PARP, ATR,
ATM, DNA-PKcs, WEE1, CDK12, RAD51, RAD52, and PD-1) and discusses
the medicinal chemistry programs being used to interrogate them, the
challenges these programs face, and what the future holds for this
promising field.