Selective Inhibition of HDAC6: The Antitumor Potential of CVL608 in Preclinical Tumor Models

A new class of HDAC6 selective inhibitors, known as CVL608, has been developed and evaluated for its antitumor properties against both non-solid and solid tumors. These inhibitors have been shown to be more potent and less toxic than non-selective HDAC inhibitors, which are often linked to heart, blood, and digestive system side effects. The CVL608 series demonstrated high selectivity for HDAC6 over other subtypes, with an IC50 less than 10 micromoles against a variety of cancer cell lines, matching or outperforming the clinical candidate ACY-241.

The evaluation methods included HDAC enzyme inhibition screening using Caliper technology and assessing the compounds' anti-proliferative effects on multiple cancer cell lines. In vivo studies were conducted on mouse models to test the efficacy of CVL608 as a single agent and in combination with chemotherapy and proteasome inhibitors, as well as checkpoint inhibitors.

The results indicated that CVL608 compounds showed a 5-20 times higher selectivity for HDAC6 than HDAC3 and 20-100 times higher selectivity over HDAC1 and HDAC8, with potency against HDAC6 at less than 5 nanomolar. In the MM.1s cancer model, CVL608 was more effective at inhibiting tumor growth than ACY-241 when used alone at a dosage of 30mg/kg. Additionally, when combined with Bortezomib, CVL608 significantly reduced tumor growth compared to monotherapy and the combination of ACY-241 with Bortezomib.

Further studies are underway to investigate the effects of CVL608 in combination with paclitaxel in breast cancer models and with PD-1 inhibitors in lung and melanoma cancer models. The findings suggest that CVL608 has the potential for clinical development as a novel HDAC6 selective inhibitor for the treatment of both non-solid and solid tumors. The research was presented at the Annual Meeting of the American Association for Cancer Research in 2020.