Abstract
Epigenetic targeting has emerged as an efficacious therapy for hematological cancers. The rare and incurable T-cell prolymphocytic leukemia (T-PLL) is known for its aggressive clinical course. Current epigenetic agents such as histone deacetylase (HDAC) inhibitors are increasingly used for targeted therapy. Through a structure–activity relationship (SAR) study, we developed an HDAC6 inhibitor KT-531, which exhibited higher potency in T-PLL compared to other hematological cancers. KT-531 displayed strong HDAC6 inhibitory potency and selectivity, on-target biological activity, and a safe therapeutic window in nontransformed cell lines. In primary T-PLL patient cells, where HDAC6 was found to be overexpressed, KT-531 exhibited strong biological responses, and safety in healthy donor samples. Notably, combination studies in T-PLL patient samples demonstrated KT-531 synergizes with approved cancer drugs, bendamustine, idasanutlin, and venetoclax. Our work suggests HDAC inhibition in T-PLL could afford sufficient therapeutic windows to achieve durable remission either as stand-alone or in combination with targeted drugs.
Highlights
Epigenetic regulation of gene expression in the onset and progression of cancer has fueled therapeutic strategies against a number of molecular targets
A comprehensive structure−activity relationship (SAR) study of 1 was designed to identify inhibitors that retained/amplified HDAC6 potency and selectivity, while improving the limited pharmacokinetic (PK) profile which precluded its advancement to preclinical studies (Figure 1a,b).[47]
In order to synthesize a subset of the desired inhibitor library using Scheme 1a, 4-formyl benzoic acid was protected using benzyl bromide to form benzyl 4-formylbenzoate (S1) (70%), which was reductively aminated with the appropriate amines to form the desired secondary amine (S2, S2c) (83%)
Summary
Epigenetic regulation of gene expression in the onset and progression of cancer has fueled therapeutic strategies against a number of molecular targets. The prepared library (Figure 1a) was screened against HDAC3, 6, 8, 11 (representative of groups I, II, and IV) to determine in vitro activity inhibition profiles (Figure 1b).[48,49] Concurrently, cellular activity was analyzed in a model cancer cell line (MV4-11) and healthy fibroblasts (MRC-9) to correlate biochemical inhibition with cellular potency and therapeutic window, and other HDACi (SAHA/vorinostat, ricolinostat, and citarinostat), as well as parent compound 1, were included for parallel comparison. KT-531 displayed an IC50 of 22 μM in MRC-9 (lung) cells, revealing a clear therapeutic window This supports the improved safety profile of HDAC6-targeting inhibitors compared to panHDACi. NHF (normal human fibroblasts), HUVEC (primary human umbilical vein endothelial cells), and pPF (primary pooled fibroblasts from 250 donors) were assessed against citarinostat and KT-531, and while still possessing a therapeutic window both molecules were significantly more potent in these normal cell types (Figure 6a).
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