Harnessing the Role of HDAC6 in Idiopathic Pulmonary Fibrosis: Design, Synthesis, Structural Analysis, and Biological Evaluation of Potent Inhibitors

Abstract

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by a progressive-fibrosing phenotype. IPF has been associated with aberrant HDAC activities confirmed by our immunohistochemistry studies on HDAC6 overexpression in IPF lung tissues. We herein developed a series of novel hHDAC6 inhibitors, having low inhibitory potency over hHDAC1 and hHDAC8, as potential pharmacological tools for IPF treatment. Their inhibitory potency was combined with low in vitro and in vivo toxicity. Structural analysis of 6h and structure− activity relationship studies contributed to the optimization of the binding mode of the new molecules. The best-performing analogues were tested for their efficacy in inhibiting fibrotic sphere formation and cell viability, proving their capability in reverting the IPF phenotype. The efficacy of analogue 6h was also determined in a validated human lung model of TGF-β1dependent fibrogenesis. The results highlighted in this manuscript may pave the way for the identification of first-in-class molecules for the treatment of IPF.

Novel Labdane Diterpenes-Based Synthetic Derivatives: Identification of a Bifunctional Vasodilator That Inhibits CaV1.2 and Stimulates KCa1.1 Channels

“…Spontaneously beating heart was retrogradely perfused via the aorta at a constant perfusion flow in a Langendorff apparatus (Radnoti, Dublin, Ireland) with a physiological salt solution containing (mM) NaCl 118, KCl 4.7, CaCl 2 2.5, MgSO 4 1.2, NaHCO 3 25, KH 2 PO 4 1.2, glucose 11.5, Na pyruvate 2, and EDTA 0.5, and bubbled with a 95% O 2 −5% CO 2 gas mixture (pH 7.4), and kept at 37 °C, as described elsewhere [ 42 , 43 , 44 ]. Hearts were allowed to equilibrate for at least 20 min before 7 exposure.…”

A Therapeutic Perspective of HDAC8 in Different Diseases: An Overview of Selective Inhibitors

“…However, selective HDAC8 inhibition over HDAC6 proved to be more challenging, due to the structural similarities in the active site [ 20 , 21 ]. In contrast with HDAC8, L6 and L1 loops in HDAC6 isoform are able to form a larger and shallower groove that preferentially accommodates Y-shaped inhibitors endowed with extended and bulky cap groups ( Figure 2 ) [ 22 , 23 ]. Briefly, the principal differences that define HDAC8 as a unique isoform are the following: HDAC8 is an X-linked protein which acts independently, e.g., without forming any co-complexes for the activity; The L1 loop of HDAC8 is closest to the enzyme active site and undergoes conformational changes, differently depending on the substrate ( Figure 2 ); L1 and L6 form a specific pocket which requires an “L” shape conformation for selective binding ( Figure 2 ); HDAC8 presents a nuclear localization sequence between the catalytic domain of the enzyme and the serine binding motif found at the end of the catalytic domain [ 24 ].…”

Chasing a Breath of Fresh Air in Cystic Fibrosis (CF): Therapeutic Potential of Selective HDAC6 Inhibitors to Tackle Multiple Pathways in CF Pathophysiology

“… 71 , 72 In this context, recently reported X-ray cocrystal structures of HDAC6 in complex with selective inhibitors will further help refining the design of novel chemical entities with improved potency and selectivity features. 69 , 73 − 76 This Perspective will examine the multifaceted role of HDAC6 in CF and highlight the potential of selective HDAC6 inhibitors as innovative therapeutic options for the treatment of several aspects of this disabling and lethal rare disease.…”

“…Accordingly, TubA was shown to protect mice from lung fibrosis by repressing TGF-β1-induced collagen expression and diminished Akt phosphorylation, 169 and novel indoline-based inhibitors demonstrated efficacy in a human lung model of TGF-β1-dependent fibrogenesis and the ability to inhibit fibrotic sphere formation. 73 …”