AZD-7648 is a potent and selective DNA-PK inhibitor. AZD7648,enhances HDR efficiency in CRISPR-Cas9 gene editing by shifting DNA repair from the error-prone NHEJ pathway to the precise HDR pathway, significantly improving gene targeting outcomes in human cells for effective ex vivo gene therapies.

NAV 2729 (NAV2729) is a chemical potentiator for mRNA-LNPs, increasing the delivery efficiencies of mRNA-LNPs in vitro and in vivo.

SH-BC-893 is a water-soluble, orally bioavailable synthetic sphingolipid that triggers nutrient transporter internalization and also blocks lysosome-dependent nutrient generation pathways in cancer cells, activates protein phosphatase 2A (PP2A), leading to mislocalization of the lipid kinase PIKfyve; selectively kills cells expressing an activated form of the anabolic oncogene Ras in vitro and in vivo.SH-BC-893, increases the activity of antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) up to 200-fold in vitro without permeabilizing endosomes. SH-BC-893 treatment trapped endocytosed oligonucleotides within extra-lysosomal compartments thought to be more permeable due to frequent membrane fission and fusion events. Simultaneous disruption of ARF6-dependent endocytic recycling and PIKfyve-dependent lysosomal fusion was necessary and sufficient for SH-BC-893 to increase non-lysosomal oligonucleotide levels and enhance their activity. In mice, oral administration of SH-BC-893 increased ASO potency in the liver by 15-fold without toxicity. More importantly, SH-BC-893 enabled target RNA knockdown in the CNS and lungs of mice treated subcutaneously with cholesterol-functionalized duplexed oligonucleotides or unmodified ASOs, respectively. Together, these results establish the feasibility of using a small molecule that disrupts endolysosomal trafficking to improve the activity of oligonucleotides in extrahepatic tissues.

ART558 is a nanomolar potent, selective, low molecular weight, allosteric DNA polymerase activity of Polθ inhibitor (IC50=7.9 nM). Inhibition of TMEJ with ART558 increases the efficiency of HDR-mediated repair on Cas9-induced DSBs, most profoundly in combination with a NHEJ/DNA-PKcs inhibitor.

Endosidine 5 (ES5), is one of the most potent small molecules interferes with recycling endosomes through Annexin A6, thereby promoting the release and expression of mRNA into the cytoplasm. The delivered mRNAs is greatly enhanced via inhibition of endocytic recycling in cells and in live mice. NAV2729 (NAV) and endosidin 5 (ES5), resulted in significant enhancement (1.5–2 folds) of LNP-mediated delivery of Fluc mRNAs. Incubation of NAV and ES5 together caused modest further increases in Fluc expression in comparison to the sole application of either compound.