Zhang Xu Hannah, Hsiang Jack, Rosen Steven T
Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Beckman Research Institute, National Medical Center, Duarte, CA 91010, USA.
J Clin Haematol. 2021;2(2):48-61. doi: 10.33696/haematology.2.028. Epub 2021 May 4.
Flavopiridol (FVP; Alvocidib), a CDKs inhibitor, is currently undergoing clinical trials for treatment of leukemia and other blood cancers. Our studies demonstrated that FVP also inhibited p38 kinases activities with IC (μM) for p38α: 1.34; p38 β: 1.82; p38γ: 0.65, and p38δ: 0.45. FVP showed potent cytotoxicity in cutaneous T-cell lymphoma (CTCL) Hut78 cells, with IC <100 nM. NMR analysis revealed that FVP bound to p38γ in the ATP binding pocket, causing allosteric perturbation from sites surrounding the ATP binding pocket. Kinomic profiling with the PamGene platform in both cell-based and cell-free analysis further revealed dosage of FVP significantly affects downstream pathways in treated CTCL cells, which suggested a need for development of synergistic drugs with FVP to prevent its clinically adverse effects. It led us discover niclosamide as a synergistic drug of FVP for our future study.
黄酮哌啶醇（FVP；Alvocidib）是一种细胞周期蛋白依赖性激酶（CDKs）抑制剂，目前正在进行治疗白血病和其他血癌的临床试验。我们的研究表明，FVP还能抑制p38激酶的活性，其对p38α的IC50（μM）为1.34；对p38β为1.82；对p38γ为0.65，对p38δ为0.45。FVP在皮肤T细胞淋巴瘤（CTCL）Hut78细胞中表现出强大的细胞毒性，IC50<100 nM。核磁共振（NMR）分析表明，FVP在ATP结合口袋中与p38γ结合，导致ATP结合口袋周围位点的变构扰动。在基于细胞和无细胞分析中使用PamGene平台进行激酶组分析进一步表明，FVP的剂量显著影响经处理的CTCL细胞中的下游通路，这表明需要开发与FVP协同的药物以预防其临床不良反应。这使我们发现氯硝柳胺可作为FVP的协同药物用于我们未来的研究。
