Discovery of Novel Imidazo[1,2-a]pyridine-Based HDAC6 Inhibitors

Cardiovascular diseases associated with chemotherapy have emerged as a growing concern in recent years, known as cardio-oncology. The commonly utilized anti-tumor drugs (eg, fluorouracil, platin, anthracycline, paclitaxel) usually exhibit left ventricular systolic dysfunction. Due to the fact that the pathological mechanisms by which some cancer therapies cause left ventricular dysfunction clearly differ from the other heart diseases, therefore traditional neurohormonal inhibitors (i.e., antagonists of the renin-angiotensin-aldoste rone system), the β-adrenergic system, or their combinations exhibited limited treatment efficacy. Meanwhile, maintaining the delicate balance between anti-tumor effect and cardioprotective effect becomes challenging due to continuous weakness and tumor progression. It is imperative to explore and develop drugs that possess a low risk of cardiovascular injury or exhibit bifunctional properties encompassing both cardioprotective and anti-tumor effects for cancer patients. Histone deacetylase 6 (HDAC6) plays a crucial role in promoting proliferation, invasion, metastasis, drug resistance, and reducing the immunogenicity of tumor cells, thereby facilitating cancer progression. Currently, several HDAC6 inhibitors are being tested in clinical trials for the treatment of solid tumors (eg, KA-2507、ACY-241、ACY-1215). On the other hand, inhibiting HDAC6 can enhance cardiomyocyte resistance against exogenous or endogenous injury through multiple pathways. TN-301 (unknown structure), the first HDAC6 inhibitor developed for cardioprotection by Tenaya Pharmaceuticals, has submitted an investigational novel drug application to the FDA and EMEA in 2022. Therefore, the development of novel HDAC6 inhibitors with high efficacy and low toxicity holds great promise for future applications in cancer treatment.

This challenge is what inspired a new study led by Professor Li-Ying Ma and Professor Bo Wei and conducted by a research team at Zhengzhou University, and was recently published in the Journal of Medicinal Chemistry. Professor Ma and Wei’s team, including researchers Fei-Fei Yang, Jing-Jing Liu, Xue-Li Xu, Ting Hu, Jian-Quan Liu, Zhang-Xu He, and Guang-Yuan Zhao, discovered and explored novel imidazo[1,2-a]pyridine-based HDAC6 inhibitors as an anticarcinogen with a cardioprotective effect. In this study, researchers conducted extensive SAR studies driven by pharmacophore-based remodification and fragment-based design. Notably, the SAR studies confirmed that the inhibition of HDAC6 conferred myocardial cell protection against induced injury. Besides, several HDAC6 inhibitors containing imidazo[1,2-a]pyridine exhibited potential as anti-tumor drugs with high efficacy and low toxicity. Among them, I-c4 demonstrated the highest sensitivity to MGC-803 cell line (IC₅₀ = 0.95 ± 0.03 µM), the anti-tumor activity and cardioprotection of which surpassed that of SAHA. Moreover, I-c4 could effectively suppress the growth of MGC-803 xenografts in vitro and in vivo without causing myocardial damage after long-term administration. These findings suggested that I-c4 might represent a novel lead compound for further development of anti-gastric cancer agents with a low risk of cardiovascular injury.

Myocardial injury is a nonnegligible problem in cardiovascular diseases and cancer therapy. The production of reactive oxygen species (i.e., oxidative stress) can accelerate the death of tumour cells, but also cause myocardial injury. Therefore, researchers chose a corresponding myocardial injury model to simulate the myocardial injury induced by reactive oxygen species in anti-tumor therapies. Researchers found that I-c4 could mitigate severe myocardial damage against H₂O₂ or myocardial ischemia/reperfusion in vitro and in vivo. Further studies revealed that I-c4 might mitigate myocardial cell damage by inhibiting cardiac inflammatory marker factors(i.e. , IL-18 and IL-1β). However, different subtypes of HDACs play distinct roles in the progression of cardiovascular injury. Among them, HDAC1 has garnered attention due to its positive regulatory factors in cardiac development and pathological remodeling and its contrasting regulation mechanism compared to HDAC6. Based on the above, researchers further assessed I-c4‘s inhibitory activity against HDAC1 and conducted thermal shift experiments on both HDAC6 and HDAC1. The results indicated that I-c4 could form stable bindings with both HDAC6 and HDAC1, demonstrating dual inhibitory activity. Considering I-c4‘s excellent cardioprotective function, it is possible that the synergistic inhibition of both HDAC6 and HDAC1 reduced the adverse effects of solely targeting HDAC1, providing a foundation for further optimization of the structure-activity relationship. To further verify that the role of HDAC6 in the cardioprotective effect of I-c4, adenovirus induced HDAC6 overexpression was used only to find that I-c4 markedly blocked the unfavorable action and pro-inflammatory effect of HDAC6. The results showed that I-c4 could exert cardioprotective effect through HDAC6.

In conclusion, to explore highly effective anti-tumor drugs with a low risk of cardiovascular injury, researchers discovered that a class of novel HDAC6 inhibitors with imidazo[1,2-a]pyridine skeleton, which exhibited remarkable efficacy in both cardioprotective and anti-gastric cancer effects. The above studies inspired new insights into the regulatory mechanism involving histone deacetylase association in onco-cardiology. Considering the current advancements in domestic and international research, it is crucial to further explore the combination of HDAC6 inhibitors with conventional chemotherapy drugs to mitigate myocardial injury.