ABSTRACT
In recent years, synthetic lethality has been recognized as a solid paradigm for anticancer therapies. The discovery of a growing number of synthetic lethal targets has led to a significant expansion in the use of synthetic lethality, far beyond poly(ADP-ribose) polymerase inhibitors used to treat BRCA1/2-defective tumors. In particular, molecular targets within DNA damage response have provided a source of inhibitors that have rapidly reached clinical trials. This Perspective focuses on the most recent progress in synthetic lethal targets and their inhibitors, within and beyond the DNA damage response, describing their design and associated therapeutic strategies. We will conclude by discussing the current challenges and new opportunities for this promising field of research, to stimulate discussion in the medicinal chemistry community, allowing the investigation of synthetic lethality to reach its full potential.
Subject(s)
Antineoplastic Agents , DNA Damage , Neoplasms , Synthetic Lethal Mutations , Humans , Neoplasms/drug therapy , Neoplasms/pathology , Neoplasms/genetics , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/chemical synthesis , DNA Damage/drug effects , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Poly(ADP-ribose) Polymerase Inhibitors/chemistry , AnimalsABSTRACT
The BRCA2-RAD51 interaction remains an intriguing target for cancer drug discovery due to its vital role in DNA damage repair mechanisms, which cancer cells become particularly reliant on. Moreover, RAD51 has many synthetically lethal partners, including PARP1-2, which can be exploited to induce synthetic lethality in cancer. In this study, we established a 19F-NMR-fragment based approach to identify RAD51 binders, leading to two initial hits. A subsequent SAR program identified 46 as a low micromolar inhibitor of the BRCA2-RAD51 interaction. 46 was tested in different pancreatic cancer cell lines, to evaluate its ability to inhibit the homologous recombination DNA repair pathway, mediated by BRCA2-RAD51 and trigger synthetic lethality in combination with the PARP inhibitor talazoparib, through the induction of apoptosis. Moreover, we further analyzed the 46/talazoparib combination in 3D pancreatic cancer models. Overall, 46 showed its potential as a tool to evaluate the RAD51/PARP1-2 synthetic lethality mechanism, along with providing a prospect for further inhibitors development.
Subject(s)
Antineoplastic Agents , Pancreatic Neoplasms , Humans , Antineoplastic Agents/chemistry , BRCA2 Protein/antagonists & inhibitors , BRCA2 Protein/metabolism , Cell Line, Tumor , DNA Repair , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/genetics , Poly(ADP-ribose) Polymerase Inhibitors/chemistry , Rad51 Recombinase/antagonists & inhibitors , Rad51 Recombinase/metabolism , Synthetic Lethal MutationsABSTRACT
In recent years, the RAD52 protein has been highlighted as a mediator of many DNA repair mechanisms. While RAD52 was initially considered to be a non-essential auxiliary factor, its inhibition has more recently been demonstrated to be synthetically lethal in cancer cells bearing mutations and inactivation of specific intracellular pathways, such as homologous recombination. RAD52 is now recognized as a novel and critical pharmacological target. In this review, we comprehensively describe the available structural and functional information on RAD52. The review highlights the pathways in which RAD52 is involved and the approaches to RAD52 inhibition. We discuss the multifaceted role of this protein, which has a complex, dynamic, and functional 3D superstructural arrangement. This complexity reinforces the need to further investigate and characterize RAD52 to solve a challenging mechanistic puzzle and pave the way for a robust drug discovery campaign.