Abstract: Screening methods as well as kits for identifying compounds capable of trapping proteins, e.g. proteins involved in DNA repair, are provided. The methods provide the use of live-cell imaging and local laser micro-irradiation of nuclear DNA in an assay to measure the effects of compounds on the trapping of 5 proteins on DNA. The disruption, e.g. inhibition, of specific proteins, such as poly-(ADP-ribose) polymerases or ALC1 enzyme, leads to trapping on chromatin and/or at DNA damage sites. This inhibits essential cellular functions, e.g. DNA damage repair, and can potentiate cancer cell killing.

Abstract: The present invention relates to small molecule compounds that allosterically inhibit ALC1 (CHD1L) and which induce the trapping of PARP1, PARP2 and/or PARP3 on chromatin or at DNA damage sites. Disruption of the chromatin remodeling forces of ALC1 through these agents enables a highly selective therapy for targeting the DNA damage functions of PARP enzymes in several proliferative diseases, notably BRCA-deficient cancers. Via inhibition of the enzymatic activity, the compounds engage the synthetic lethality between BRCA1/2 and ALC1. By trapping PARP enzymes, inhibitors of ALC1 potentiate the cancer cell killing properties of PARP inhibitors, enable therapeutic approaches where ALC1 is amplified as an oncogene, therapeutically make it possible to overcome PARP inhibitor resistance mechanisms and enable an alternative approach to the treatment of germline or acquired BRCA1/BRCA2 deficiency, including tumors defined by “BRCAness” or other changes in DNA repair networks.

Abstract: The present invention relates to a method for diagnosing the risk of cancer recurrence in a mammalian patient, comprising detecting the expression of macroH2A1.1 and/or macroH2A2 in a biological sample obtained from said patient, wherein a low or reduced expression of said macroH2A1.1 and/or macroH2A2 is indicative for an increased risk of cancer recurrence in said patient. The present invention is further directed at improved methods for treating cancer, in particular breast and/or lung cancer, based on said diagnostic method.