Abstract Body (Do not enter title and authors here): Background: HFpEF is a complex and prevalent condition with few effective treatments. HDAC6 regulates several biological processes, including autophagy, mitochondrial function and inflammation, through deacetylation of non-histone proteins, but its impact and therapeutic potential in HFpEF have not been thoroughly evaluated. We investigated the efficacy of a highly potent and selective small molecule HDAC6 inhibitor, EKZ-102, in a "two-hit" HFpEF mouse model. EKZ-102 possesses several advantageous characteristics including a next-generation oxadiazole Zn²⁺-binding domain, low nanomolar activity, remarkable selectivity for HDAC6 over all other HDAC paralogs (>1,000-fold), favorable bioavailability with the potential for once daily oral dosing, and CNS penetrance. Furthermore, EKZ-102 exhibits a clean in vitro safety profile and no observed adverse effects levels (NOAELs) have been identified in rodent and non-rodent species in 28-day GLP toxicology studies, poising EKZ-102 for clinical assessment.
Methods: HFpEF was induced in 10-week-old male C57BL/6N mice using HFD combined with the NOS inhibitor L-NAME (1.5 g/kg). After 5 weeks, mice were randomized to receive daily oral gavage of either vehicle (1% CMC), empagliflozin (10 mg/kg), or EKZ-102 (30 mg/kg) for 10 weeks. We assessed the effects of treatment on body weight, echocardiographic indices of cardiac function, treadmill exercise capacity, and invasive systemic and LV pressures.
Results: Echocardiography confirmed preserved LVEF across all groups. Following 10 weeks of treatment, HDAC6 inhibition significantly reduced the E/e' ratio compared to HFpEF controls, with effects comparable to the clinically approved SGLT2 inhibitor treatment, empagliflozin. Vehicle-treated mice exhibited deteriorated treadmill exercise running distance and work; notably, HDAC6 inhibition with EKZ-102 significantly improved both of these clinically relevant markers, mirroring the improvements seen with empagliflozin. While no treatment affected systemic blood pressure, EKZ-102 treatment significantly reduced LVEDP compared to vehicle controls, a benefit not statistically significant with empagliflozin.
Conclusion: Our findings demonstrate that pharmacological inhibition of HDAC6 with EKZ-102 improves key pathological and functional deficits in a well-established mouse model of HFpEF. These results highlight HDAC6 as a promising therapeutic target for HFpEF and warrant further investigation into EKZ-102's clinical potential.