Targeting cyclin-dependent kinases 4/6 inhibits survival of megakaryoblasts in acute megakaryoblastic leukaemia

Qi, Kunming; Hu, Xueting; Yu, Xiangru; Cheng, Hai; Wang, Chunqing; Wang, Shujin; Wang, Ying; Li, Yanjie; Cao, Jiashu; Peng, Bin; Wu, Qingyun; Qiao, Jianlin; Zeng, Lingyu; Li, Zhenyu; Xu, Kailin; Fu, Chunling

doi:10.1016/j.leukres.2022.106920

Cited by 2 publications

(1 citation statement)

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“…When CDK4/6 is inhibited, the G1 phase of proliferating cells is blocked ( Yuan et al, 2021 ; Chen et al, 2022 ; Watt and Goel, 2022 ; Yousuf et al, 2022 ). Additionally, CDK4/6 is disordered in numerous cancers ( Wesierska-Gadek et al, 2009 ; Sanchez-Martinez et al, 2019 ; Yuan et al, 2021 ; Ghafouri-Fard et al, 2022 ; Kargbo, 2022 ; Yousuf et al, 2022 ; Zabihi et al, 2022 ), such as breast cancer ( Gelbert et al, 2014 ; Chen et al, 2022 ; Watt and Goel, 2022 ), osteosarcoma ( Wang and Bao, 2022 ), and acute megakaryoblastic leukemia ( Qi et al, 2022 ). Thus, CDK4/6 is an effective anticancer drug target, especially in hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer.…”

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confidence: 99%

Identification of abemaciclib derivatives targeting cyclin-dependent kinase 4 and 6 using molecular dynamics, binding free energy calculation, synthesis, and pharmacological evaluation

Zhou

Luo

et al. 2023

Front. Pharmacol.

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CDK4/6 plays a crucial role in various cancers and is an effective anticancer drug target. However, the gap between clinical requirements and approved CDK4/6 drugs is unresolved. Thus, there is an urgent need to develop selective and oral CDK4/6 inhibitors, particularly for monotherapy. Here, we studied the interaction between abemaciclib and human CDK6 using molecular dynamics simulations, binding free energy calculations, and energy decomposition. V101 and H100 formed stable hydrogen bonds with the amine-pyrimidine group, and K43 interacted with the imidazole ring via an unstable hydrogen bond. Meanwhile, I19, V27, A41, and L152 interacted with abemaciclib through π-alkyl interactions. Based on the binding model, abemaciclib was divided into four regions. With one region modification, 43 compounds were designed and evaluated using molecular docking. From each region, three favorable groups were selected and combined with each other to obtain 81 compounds. Among them, C2231-A, which was obtained by removing the methylene group from C2231, showed better inhibition than C2231. Kinase profiling revealed that C2231-A showed inhibitory activity similar to that of abemaciclib; additionally, C2231-A inhibited the growth of MDA-MB-231 cells to a greater extent than did abemaciclib. Based on molecular dynamics simulation, C2231-A was identified as a promising candidate compound with considerable inhibitory effects on human breast cancer cell lines.

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