ALC1 inhibitors and synergy with PARPi

The present invention relates to small molecule compounds that allosteric inhibit ALC1 (CHD1L) and induce the capture of PARP1, PARP2 and/or PARP3 on chromatin or at a DNA damage site. In several proliferative diseases, especially BRCA-deficient cancers, disruption of the chromatin remodeling force of ALC1 by these agents achieves highly selective therapies for the DNA damage function of the targeted PARP enzyme. Via inhibition of enzymatic activity, the compound participates in synthetic lethal between BRCA1/2 and ALC1. By capturing PARP enzyme, the inhibitor of ALC1 enhances the cancer cell killing characteristic of the PARP inhibitor, a treatment method under the condition that ALC1 is used for oncogene amplification is realized, and overcoming of the drug resistance mechanism of the PARP inhibitor becomes possible in treatment; and enables an alternative approach to the treatment of germline or acquired BRCA1/BRCA2 defects, including tumors defined by "BRCANs" or other changes in the DNA repair network. 本