Development of HDAC Inhibitors Exhibiting Therapeutic Potential in T-Cell Prolymphocytic Leukemia

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.

Discovery of HDAC6-Selective Inhibitor NN-390 with in Vitro Efficacy in Group 3 Medulloblastoma

“…53 Other fluorination/halogenation patterns were also tested in a recent SAR study, which revealed that the tetrafluoro analogs demonstrated superiority in terms of HDAC6 potency, selectivity, and cellular efficacy. 54 Compound 5a retained potency in the functional inhibition assay (Electrophoretic mobility shift assay (EMSA), Nanosyn Inc., USA) against HDAC6 (IC 50 = 9.8 nM) with 207-fold selectivity for HDAC6 over the next most potently hit HDAC (all 11 Zn 2+ -dependent HDAC isozymes evaluated). This compared favorably to the Given the promising data, an SAR test of the parent scaffold was conducted (Tables 1 and 2 and Table S2).…”

“…First, since HDAC6 does not have a reactive and accessible cysteine proximal to the catalytic tunnel, the electron-deficient electrophilic pentafluorobenzene sulfonamide (PFBS) group was considered an unnecessary metabolic liability and prompted the design of the less reactive N -hydroxy-4-(((2,3,4,5-tetrafluoro- N -isopropylphenyl)­sulfonamido)­methyl)­benzamide homolog 5a ( NN-390 ) . Other fluorination/halogenation patterns were also tested in a recent SAR study, which revealed that the tetrafluoro analogs demonstrated superiority in terms of HDAC6 potency, selectivity, and cellular efficacy . Compound 5a retained potency in the functional inhibition assay (Electrophoretic mobility shift assay (EMSA), Nanosyn Inc., USA) against HDAC6 (IC 50 = 9.8 nM) with 207-fold selectivity for HDAC6 over the next most potently hit HDAC (all 11 Zn 2+ -dependent HDAC isozymes evaluated).…”

Virtual Special Issue: Epigenetics 2022

“…61 The lysine/histone deacetylases (K/HDAC) are an established epigenetic therapeutic target. In this collection there are reports of HDAC inhibitors being investigated for the treatment of T-cell prolymphocytic leukemia 62 and the repurposing of human HDAC6 inhibitors to treat multi-drugresistant malaria-causing parasites. 63 There is also a Perspective discussing the potential for using selective HDAC6 inhibitors as a treatment for aspects of cystic fibrosis-associated lung disease.…”

Virtual Special Issue: Epigenetics 2022

“…The lysine/histone deacetylases (K/HDAC) are an established epigenetic therapeutic target. In this collection there are reports of HDAC inhibitors being investigated for the treatment of T-cell prolympho­cytic leukemia and the repurposing of human HDAC6 inhibitors to treat multi-drug-resistant malaria-causing parasites . There is also a Perspective discussing the potential for using selective HDAC6 inhibitors as a treatment for aspects of cystic fibrosis-associated lung disease .…”