Abstract
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.
Highlights
It is commonly known that cancer is a disease of the genome, wherein errors in DNA replication and repair cause failures in cell function, while the mechanisms that would normally deal with these faulty cells are compromised, resulting in cancer cell survival and proliferation
CDK12 was first identified when investigating the cell cycle regulator CDC2.122 While it has structural similarities to other members of the CDK subfamily, which play a role in cell cycle regulations, CDK12 is a transcription kinase involved in the transcription of genes involved in DNA repair,[123] regulating specific genes that respond to stress, heat shock, and DNA damage.[124]
RAD51 is a member of the RAD52 epistasis group, which is made up of RAD50, RAD51, RAD52, RAD54, RAD55, RAD57, RAD59, MRE11, and XRS2.140 In vitro studies have shown that RAD51 promotes homologous pairing and strand transfer reactions
Summary
It is commonly known that cancer is a disease of the genome, wherein errors in DNA replication and repair cause failures in cell function, while the mechanisms that would normally deal with these faulty cells are compromised, resulting in cancer cell survival and proliferation. A combination study to determine the overall response rate of 6 and irinotecan in participants with progressive, metastatic, or unresectable TP53 mutant gastric or gastroesophageal junction cancer It seeks to assess the duration of response, time to progression, progression-free survival, and OS in participants with the combination of drugs in comparison to irinotecan alone and in participants with other DNA damage repair defects such as mutations in RCA1, BRCA2, MRE11, RAD50, RAD51, RAD52, RAD54L, NBN, ATM, H2AX, PALB2, RPA, BRIP1, BARD1, ATR, ATRX, CHK1, CHK2, MDM2, MDM4, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG and FANCL. I/II A combination study that evaluates the safety, pharmacokinetics, pharmacodynamics, and efficacy of acalabrutinib and 11
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