HDAC6 inhibitors(Ocean University of China)

Previously, we found that hydrazide can serve as zinc binding groups for selective HDAC6 inhibitors and identified the first hydrazide-based HDAC6 inhibitor, 35m, which exhibited modest isoform selectivity. This study aimed to improve the HDAC6 selectivity of 35m, thereby reducing its side effects. Extensive structure-activity relationship studies revealed that the introduction of fluorine atoms at the 2 and 5 positions of the linker phenyl ring in compound 35m significantly enhanced its HDAC6 selectivity while maintaining its potency. The representative compound 9m demonstrated an IC₅₀ of 0.021 μM against HDAC6, exhibiting at least 335-fold selectivity over other isoforms, along with favorable pharmacokinetic properties and improved safety profiles. Compound 9m inhibits the activation of NLRP3 inflammasome and significantly alleviates symptoms in multiple NLRP3 inflammasome-related disease models, including acute peritoneal, inflammatory bowel disease, and psoriasis. This study enriches the design strategies for selective HDAC6 inhibitors and provides a lead compound for NLRP3 inflammasome-related diseases.

DNMT3A encodes a DNA methyltransferase involved in development, cell differentiation, and gene transcription, which is mutated and aberrant-expressed in cancers. Here, we revealed that loss of DNMT3A promotes malignant phenotypes in lung cancer. Based on the epigenetic inhibitor library synthetic lethal screening, we found that small-molecule HDAC6 inhibitors selectively killed DNMT3A-defective NSCLC cells. Knockdown of HDAC6 by siRNAs reduced cell growth and induced apoptosis in DNMT3A-defective NSCLC cells. However, sensitive cells became resistant when DNMT3A was rescued. Furthermore, the selectivity to HDAC6 inhibition was recapitulated in mice, where an HDAC6 inhibitor retarded tumor growth established from DNMT3A-defective but not DNMT3A parental NSCLC cells. Mechanistically, DNMT3A loss resulted in the upregulation of HDAC6 through decreasing its promoter CpG methylation and enhancing transcription factor RUNX1 binding. Notably, our results indicated that HIF-1 pathway was activated in DNMT3A-defective cells whereas inactivated by HDAC6 inhibition. Knockout of HIF-1 contributed to the elimination of synthetic lethality between DNMT3A and HDAC6. Interestingly, HIF-1 pathway inhibitors could mimic the selective efficacy of HDAC6 inhibition in DNMT3A-defective cells. These results demonstrated HDAC6 as a HIF-1-dependent vulnerability of DNMT3A-defective cancers. Together, our findings identify HDAC6 as a potential HIF-1-dependent therapeutic target for the treatment of DNMT3A-defective cancers like NSCLC.