The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300071, PR China.
Department of Hematology and Oncology, International Cancer Center, Shenzhen Key Laboratory of Precision Medicine for Hematological Malignancies, Shenzhen University General Hospital, Shenzhen University Clinical Medical Academy, Shenzhen, Guangdong, 518000, PR China.
Eur J Med Chem. 2023 Mar 5;249:115140. doi: 10.1016/j.ejmech.2023.115140. Epub 2023 Jan 21.
Acute myeloid leukemia (AML) has been confirmed as one of the most lethal heterogeneous clonal diseases. In addition to being essential for the development and progression of leukemia, leukemic stem cells (LSCs), a subpopulation of leukemia cells with stem cell characteristics, are also primarily responsible for the development of leukemia relapse and drug resistance. Elimination of stemness and induction of AML cell differentiation would become a promising and effective therapeutic strategy. In the present study, a novel class of HDACs/CDKs dual inhibitors was prepared and optimized. An active compound 33a has been identified, which exhibited potent and selective inhibition of CDK9, CDK12, CDK13, HDAC1, HDAC2 and HDAC3 at low nanomolar concentrations and significantly induced differentiation of leukemic stem-like cells and inhibited AML proliferation. Furthermore, the lead compound has relatively adequate oral bioavailability, suggesting that it might be used as a novel strategy to reduce the burden of LSCs and improve the prognosis for AML.
急性髓细胞白血病 (AML) 已被确认为最致命的异质性克隆疾病之一。除了对白血病的发生和发展至关重要外，白血病干细胞 (LSCs) 作为具有干细胞特征的白血病细胞亚群，也是导致白血病复发和耐药的主要原因。消除干细胞特性并诱导 AML 细胞分化将成为一种有前途且有效的治疗策略。在本研究中，制备并优化了一类新型的 HDACs/CDKs 双重抑制剂。鉴定出一种活性化合物 33a，它在低纳摩尔浓度下对 CDK9、CDK12、CDK13、HDAC1、HDAC2 和 HDAC3 具有强大且选择性的抑制作用，并能显著诱导白血病样干细胞分化，抑制 AML 增殖。此外，该先导化合物具有相对充足的口服生物利用度，表明它可能被用作一种新策略，以减轻 LSCs 的负担并改善 AML 的预后。
