Selective inhibition of Class I HDACs has emerged as a promising approach for cancer therapy. Building on our previous work with Largazole (a member of the natural depsipeptide family), we have applied a similar fluorination modification to Romidepsin and synthesized its fluoro analog (12) in 12 steps. This analog exhibits potent inhibitory activity against Class I HDACs but shows no inhibitory effect on HDAC6, confirming its selectivity as a Class I HDAC inhibitor (IC50 HDAC1 0.95 nM, HDAC2 0.86, HDAC 3 1.1 nM, HDAC8 4.2 nM, HDAC6 > 103 nM). Compared with Romidepsin, compound 12 demonstrates significant growth inhibition in two cancer cell lines (NCI-H1975 and HT29) while exhibiting markedly less growth inhibition in two normal cell lines (WRL-68 and HEK293). Further studies reveal that 12 is capable of blocking the cell cycle and inducing apoptosis, thereby exerting anticancer activity. Moreover, 12 possesses metabolic stability comparable to Romidepsin. In a mouse model, 12 demonstrates strong in vivo antitumor efficacy similar to that of Romidepsin, yet with significantly reduced toxicity. These findings support the potential of this fluoro analog as a highly selective Class I HDAC inhibitor and highlight its promise as a superior alternative to Romidepsin for further development.

14 Feb 2025·ACS Pharmacology & Translational Science

Spirotetrahydroisoquinoline-Based Histone Deacetylase Inhibitors as New Antifibrotic Agents: Biological Evaluation in Human Fibroblasts from Bronchoalveolar Lavages of Idiopathic Pulmonary Fibrosis Patients

Article

Author: Carullo, Gabriele ; Vincenzi, Fabrizio ; Pistocchi, Anna ; Saponara, Simona ; Bargagli, Elena ; Carbone, Sabrina ; Bergantini, Laura ; Papulino, Chiara ; Scalvini, Laura ; Gangi, Sara ; Fontana, Anna ; Varani, Katia ; Mor, Marco ; Contri, Chiara ; Campiani, Giuseppe ; Benedetti, Rosaria ; Cameli, Paolo ; Lodola, Alessio ; Pezzotta, Alex ; Pasquini, Silvia ; Altucci, Lucia ; Butini, Stefania ; D’Alessandro, Miriana ; Gemma, Sandra

Idiopathic pulmonary fibrosis (IPF) is a rare interstitial lung disease typified by a progressive fibrosing phenotype. IPF has been associated with aberrant HDAC activity, particularly HDAC6. Combining synthetic and modeling studies, a new family of spirotetrahydroisoquinoline-capped histone deacetylase inhibitors 5a-o was developed. These analogues were prepared via the three-component Castagnoli-Cushman reaction (CCR) as the key step. Structure-activity relationship (SAR) studies identified 5n (fibrostat) as a preferential HDAC6 inhibitor with a suitable degree of selectivity compared to HDAC1, HDAC3, HDAC5, HDAC8, HDAC10, and HDAC11. 5n was able to negatively modulate the expression of fibrotic markers, fibronectin and collagen 1, in fibroblasts derived from bronchoalveolar lavages of IPF patients. In another ex vivo IPF human model, 5n (fibrostat) reduced the expression of fibronectin and negatively affected the expression of collagen 1 and vimentin, the latter being associated with invasiveness. Finally, fibrostat did not show toxicity in rat-perfused heart and zebrafish larvae.

16 Dec 2024·Journal of Biomolecular Structure and Dynamics

Integrated molecular modeling and dynamics approaches revealed the mechanism of selective inhibition of HDAC6/8

Article

Author: Li, Yaxin ; Liu, Sisi ; Hu, Liming ; Xu, Jiamin ; Yang, Leifu ; Xu, Ximing

The high structural homology of histone deacetylases 6 and 8 (HDAC6/8) poses a challenge in achieving isoform selectivity and has resulted in adverse side effects due to pan-inhibition in clinical applications. Additionally, the rational design of dual-target inhibitors, centered on HDAC6/8, demands a profound understanding of their selectivity mechanisms. Addressing the urgent need for enhanced specificity in the development of inhibitors targeting specific isoforms, we elucidate the mechanism underpinning the selective inhibition of HDAC6/8 inhibitors through in-silico strategies. The hydrogen bonding interaction with Asp101 and Tyr306 is a key factor that enables compound 12b to selectively inhibit HDAC8. Its favorable spatial orientation places the Cap group of 12b between Tyr306 and Tyr100, resulting in an overall L-shaped conformation. These two factors significantly contribute to the selective inhibitory activity of 12b against HDAC8. The zinc binding group (ZBG) of compound NN-390 forms a hydrogen bond with His610, a key residue of HDAC6, facilitating stable chelation with zinc ions. In addition, the Cap group of NN-390 interacts with Phe620 and Phe680 via van der Waals forces, leading to an overall Y-shaped conformation. The aforementioned factors are the main reasons for the selective inhibition of HDAC6 by NN-390. Furthermore, whether the Cap group is in the para or meta-position will influence the selective inhibition of either HDAC6 or HDAC8. We believe these clues can offer valuable insights for the rational design of selective inhibitors targeting HDAC6/8 and pave the way for rational design of dual-target HDAC6/8-based inhibitors.Communicated by Ramaswamy H. Sarma.

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