Discovery of 4,5-dihydro-benzo[g]indazole-based hydroxamic acids as HDAC3/BRD4 dual inhibitors and anti-tumor agents

Concurrent inhibition of HDAC and BRD4, two well-established epigenetic targets for anti-tumor therapy, demonstrates the potential to enhance anti-tumor effects synergistically. The present study involves the development of a series of novel HDAC3/BRD4 dual inhibitors, followed by evaluation of their antitumor efficacy against several tumor models. Guided by scaffold hopping strategy, key pharmacophore of BRD4 inhibitor I-BET-151 was incorporated into an in-house developed HDAC3-selective inhibitor 17h. A set of twenty-two compounds was synthesized and characterized. Most of these compounds demonstrated significant potency in inhibiting HDAC3 and exhibited selectivity over its closely-related isoform, HDAC1. The potent BRD4 inhibition of these compounds has been further confirmed through HTFR and thermal shift assays. Of which, compounds 26b and 26n demonstrated potent dual inhibition against HDAC3 and BRD4. Compound 26n demonstrated potent antiproliferative effects against a panel of cancer cells, with human pancreatic cancer cell line Capan-1 displaying the highest susceptibility. Compound 26n exhibited significant upregulation of Ac-H3 and downregulation of c-Myc at concentrations as low as 1 μM, suggesting proper target engagement in Capan-1 cells. Compound 26n demonstrated significant antitumor efficacy in Capan-1 CDX model, with a tumor growth inhibition rate of 71% under the given dosing regimen. In summary, this research highlights the promising therapeutic potential of benzodihydroindazole derivatives as HDAC3/BRD4 dual inhibitors, warranting further investigation.