Small-molecule enhancers of CRISPR-induced homology-directed repair in gene therapy: a medicinal chemist’s perspective

•Small molecules can tip the balance in favor of the HDR pathway over the NHEJ pathway.•Cell cycle inhibitors and HDAC inhibitors can indirectly enhance precise editing.•Many of the compounds need more testing to verify improvement in precise editing.•Existing drugs of many indications could be repurposed to inhibit the NHEJ pathway.•Requirements for small molecules would be more stringent for in vivo usage. CRISPR technologies are increasingly being investigated and utilized for the treatment of human genetic diseases via genome editing. CRISPR-Cas9 first generates a targeted DNA double-stranded break, and a functional gene can then be introduced to replace the defective copy in a precise manner by templated repair via the homology-directed repair (HDR) pathway. However, this is challenging owing to the relatively low efficiency of the HDR pathway compared with a rival random repair pathway known as non-homologous end joining (NHEJ). Small molecules can be employed to increase the efficiency of HDR and decrease that of NHEJ to improve the efficiency of precise knock-in genome editing. This review discusses the potential usage of such small molecules in the context of gene therapy and their drug-likeness, from a medicinal chemist’s perspective.