Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, Ontario L5L 1C6, Canada.
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada.
J Med Chem. 2021 Jun 24;64(12):8486-8509. doi: 10.1021/acs.jmedchem.1c00420. Epub 2021 Jun 8.
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 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.
表观遗传学靶向已成为治疗血液系统恶性肿瘤的有效方法。罕见且无法治愈的 T 细胞前淋巴细胞白血病（T-PLL）以其侵袭性的临床病程而闻名。目前，组蛋白去乙酰化酶（HDAC）抑制剂等表观遗传药物越来越多地被用于靶向治疗。通过构效关系（SAR）研究，我们开发了一种 HDAC6 抑制剂 KT-531，与其他血液系统恶性肿瘤相比，它在 T-PLL 中的活性更高。KT-531 在未转化的细胞系中显示出较强的 HDAC6 抑制活性和选择性、靶标生物活性和安全的治疗窗。在原发性 T-PLL 患者细胞中，发现 过度表达，KT-531 表现出强烈的生物学反应和健康供体样本中的安全性。值得注意的是，在 T-PLL 患者样本中的联合研究表明，KT-531 与已批准的癌症药物苯达莫司汀、伊沙那汀和维奈托克协同作用。我们的工作表明，在 T-PLL 中抑制 HDAC 可能提供足够的治疗窗，以实现单独或与靶向药物联合的持久缓解。
